Orthobiologics are exciting tools providing promising results for difficult orthopedic conditions. In the elbow there is high-level evidence for their use in lateral epicondylopathy and encouraging evidence for other elbow pathologies. This article provides an in-depth review of the current literature for the use of orthobiologics in elbow injuries.
Several orthobiologic options exist for various injuries in the elbow.
Level 1 evidence is present for the use of platelet-rich plasma for lateral epicondylopathy.
Orthobiologics are safe alternatives to traditional nonsurgical options for elbow injuries.
What Is Regenerative Medicine
Regenerative medicine is a relatively young field of medicine in which a patient’s own growth factors and cells are used to promote or enhance tissue healing. The products used in regenerative medicine are referred to as orthobiologics. It is an evolving field with many indications in specialties including, but not limited to, cardiology, plastic surgery, orthopedics, and sports medicine. The first orthobiologic described in the literature was platelet-rich plasma (PRP) in 1970 and subsequently used in vivo in 1987 intraoperatively during cardiac surgery. The applications of PRP have since advanced within orthopedics especially over the last decade. PRP is now routinely used to treat tendon, ligament, and cartilage injuries.
In the search for an orthobiologic product that could potentially have a higher concentration of growth factors, mesenchymal stem cells (MSCs) have been studied for their healing potentials. MSCs can be obtained from bone marrow, adipose tissue, and from the amniotic membrane of a placenta, among other tissues. They have a very strict cellular expression; thus, they are difficult to isolate in culture. Yet, they are believed to have vast orthopedic potentials due to their ability to stimulate growth and reproduce of osteoblasts, adipocytes, and chondrocytes. However, recent evidence has uncovered that these cells may not necessarily have the multipotent or differentiation potential as once thought. These cells now seem to create the environment where other cells named pericytes are recruited and have been shown to stimulate cells in the surrounding environment to replicate. Given this information, MSCs have been renamed as medicinal signaling cells (MSCs) and referred to as such throughout this article.
Furthermore, the use of PRP and MSC in regenerative medicine is still in its infancy. Nonetheless, its future role in orthopedics and sports medicine will continue evolving, with further research looking to understand the risks and benefits of using orthobiologics to heal injured tissues.
How Do Orthobiologics Work?
Orthobiologic products have a series of growth factors and bioactive proteins that contain the capacity of enhancing the healing process of an acute injury. The goal of this enhancement is to accelerate the return to regular activities and sports. In addition, physicians can use techniques such as percutaneous tenotomy and the trophic effects of these growth factors to activate the healing process of a chronically injured tissue that did not fully heal, even injuries in a chronic, degenerative, painful state. In order to understand how these regenerative medicine products work, it is of the utmost importance to have a solid grasp of the inflammatory, proliferative, and maturation/remolding phases of wound healing ( Fig. 1 ).
For the purpose of this article, the authors use a soft tissue wound as an example. The inflammatory phase typically occurs within the first 72 hours. Platelets and white blood cells travel to the injured site to control bleeding, release growth factors that stimulate healing, and clean up necrotic debris, respectively. This phase can be initiated by injecting PRP into a chronically injured tissue, with or without including the white blood cells in the PRP product. During the proliferative phase (typically between days 3 and 42), the growth factors released by platelets attract fibroblasts and vascular proliferative cells to the injured site and stimulate them to ultimately form a new extracellular matrix of disorganized collagen fibrin. This causes contraction of soft tissue at the injury site. The third phase is the maturation or remodeling phase (occurring between 42 days and 6 months). During this phase, the scar size decreases and strength increases, reaching its peak at 6 months after the injury. Any alteration to these phases may ultimately change the outcome of the injury and delay the healing process. This may be stress induced such as returning to activity too soon or by the inappropriate use of medications that impair wound healing. Following a rehabilitation protocol that respects these three phases by protecting the tissue when needed and strengthening it when ready is paramount in achieving the optimal outcome after a treatment when using an orthobiologic.
Key Growth Factors and Signaling Cells
Platelets typically are active 5 to 9 days and are vital for proper wound healing. Platelet alpha granules contain approximately 300 bioactive substances that help prepare surrounding tissue and cells for the proliferative and remodeling phases. Injury and exposure to extracellular proteins cause activation of these platelets, leading to stimulation of the release of growth factors. The most important platelet-derived factors for wound healing are platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), insulin-like growth factor, and transforming growth factor beta (TGF-beta) ( Table 1 ). TGF-beta has been proved to recruit MSCs to the site of injury and promote chondrogenesis. , , VEGF is primarily responsible for angiogenesis, which is directly related to tissue site repair. PDGF, connective tissue growth factor, and epidermal growth factor (EGF) also work in conjunction with VEGF to accomplish the angiogenesis. Previous studies involving the use of VEGF and TGF-beta have shown improved revascularization and graft strengthening of the anterior cruciate ligament using Achilles tendon graft in animal model. Other studies have looked at the relationship of FGF-2 on the surrounding vasculature causing an improvement in chrondrogenesis. This is only a subset of a few of the important growth factors that play a role in controlled healing.
|Growth Factor||Biological Actions|
|IGF-1||Anabolic effects including protein synthesis, enhancing collagen, and matrix synthesis in the early inflammatory phase.|
|PDGF(αβ)||Assists in proliferation of growth factors by attracting stem cells and progenitor cells to stimulate tissue remodeling.|
|TGF (α-β)||A proinflammatory immunosuppressant that aids in cell migration, expression of collagen, and helps control angiogenesis and fibrosis.|
|VEGF||Promotes angiogenesis and neovascularization in the late inflammatory phase.|
|FGF||Promotes angiogenesis and neovascularization and seems to help in the regulation of cell migration and stimulate endothelial cells to produce granulation tissue during the late inflammatory phase.|
Another very important and powerful growth factor is a subset of TGF-beta called bone morphogenic proteins (BMPs). BMPs have the potential to induce large osteochondral defects (OCDs) to heal via an endochondralprocess. There is evidence in animal models of the healing potential of BMP used to treat nonunion fractures.
Finally, MSCs and pericytes have been shown to have both a systemic and a paracrine effect on tissue healing. , They have the capacity to regulate tissue healing by signaling bioactive proteins and other cells to have a trophic effect on the injured tissues. They also have an immunomodulatory effect on the injured site, specifically by suppressing inflammatory cells that may be detrimental to the healing process. ,
Clinical applications of orthobiologic products containing these growth factors and signaling cells are under further investigation for their optimal doses and possible synergistic effects. As our scientific community better understands the delicate balance of the orthobiologic products, we will be able to standardize treatments and rehabilitation protocols that appropriately stimulate tissue healing in the most optimal manner.
Percutaneous tenotomy is a procedure in which a needle is used to repeatedly penetrate a chronically diseased tendon with the goal of creating an acute inflammatory process in order to heal tissue. Over time, the technique has evolved to using novel instruments that are capable of not only providing the needle fenestration component but also removing the disease tissue. A microdebrider coblation instrument uses a radiofrequency energy that is passed through an electrically conductive fluid, such as saline, to create a controlled, stable plasma field. The instrument precisely removes tissue at a relatively low temperature, resulting in minimal thermal damage to surrounding soft tissues. In addition to the coblation instrument, an ultrasonic water jet stream device has also been used to emulsify and remove the diseased tissue via an inflow-outflow circuit.
Autologous Blood Injection
Autologous blood injection (ABI) is a procedure in which autologous blood is extracted from the patient’s peripheral venous system and injected into the injured tissue. The objective is to provide cellular and humoral mediators found in blood in order to restart the healing cascade. ,
PRP is an autologous blood product that has been concentrated via centrifugation. The end product contains a combination of powerful growth factors that has showed promising results in treating tendinopathic conditions. It has also been shown to be effective in treating osteoarthritis pain, among other conditions.
Bone Marrow Aspirate Concentrate
Bone marrow aspirate concentrate (BMAC) refers to preparations of bone marrow that have been aspirated and then centrifuged to concentrate the sample. This preparation has been shown to provide growth factors and immunomodulators without the need for laboratory culturing and processing.
Adipose-Derived Medical Signaling Cells
Adipose-derived tissue is another source being used in orthopedics for its MSC capabilities. The MSCs associated with adipose tissue are typically a part of an aqueous portion of enzymatic derived lipoaspirate; however, because of Food and Drug Administration regulations, only minimal manipulation of this product is allowed. The most common way of obtaining MSCs from the lipoaspirate occurs through nonenzymatic isolation, more specifically mechanical agitation. The product of this isolation is a stromal vascular fraction that contains growth factors similar to its hematopoietic counterparts.
Amniotic-derived products are collected from placentas of consenting women who have been screened for various diseases including human immunodeficiency virus, hepatitis, and syphilis. Following screening, the placenta is cleansed with antibiotic solution to cover the most common bacteria and fungi. Then, the amniotic membrane is separated and processed. The amniotic membrane is thought to contain an extracellular matrix that can be used as scaffold for cellular proliferation and migration. Recent literature has challenged these products being considered MSCs, given the lack of colony-forming units and plastic adherence of the cells in these preparations and the fact that most of the cells die during the preparation process.
Lateral Epicondylopathy/Common Extensor Tendinopathy
The full pathogenesis of lateral epicondylopathy is covered in another chapter in this edition; however, it is commonly referred to as “tennis elbow” and is the tendinopathy of the common extensor tendon in the elbow. It is typically seen in patients who perform strong gripping or repetitive wrist flexion and extension movements. Lateral epicondylopathy has a prevalence of 1% in the general population and as high as 50% among the recreational tennis players. , For many years, it has been described as an inflammation within the tendon or tendinitis; however, histologic studies have shown that there is a paucity in inflammatory cells. These studies revealed a degenerative process of the tendon where increased concentration of angiofibroplastic hyperplasia is present. This degenerative process occurs when the rate of injury has surpassed the rate of healing within a tendon leading to disarray of the normal architecture of the tissue.
Percutaneous needle tenotomy
There have been several studies evaluating percutaneous tenotomy for lateral epicondylopathy with promising results. One of the first investigations was done by McShane and colleagues where 58 subjects underwent ultrasound-guided percutaneous tenotomy followed by corticosteroid injection, and 80% of that cohort rated the procedure as being excellent or good at an average of 28 months following the procedure. The investigators concluded that the procedure was effective and safe, given no adverse events occurred during the study. McShane and colleagues then performed a follow-up study where 57 patients underwent the same ultrasound-guided procedure without subsequent steroid injection, and 92.3% of the patients rated the procedure as either excellent or good with a response rate of 91.2% response rate and average follow-up time of 22 months. The investigators concluded that percutaneous tenotomy without a steroid injection was an effective and safe procedure for lateral epicondylopathy based on the patients’ perception of the procedure and no reported adverse events. Fig. 2 shows an ultrasound image of a percutaneous tenotomy for lateral epicondylosis.
As mentioned earlier, other instruments have been studied that are capable of both completing the percutaneous tenotomy and also removing the diseased tissue. Koh and colleagues published initial results using an ultrasonic water jet stream device where 20 patients underwent the procedure. Nineteen of the twenty (95%) patients in the study expressed either being very satisfied or somewhat satisfied with the procedure at 1-year follow-up. Seng and colleagues performed a follow-up study of the same cohort where subjects maintained their pain reduction and functional improvements. Ultrasound findings at 36 months following the procedure also revealed decreased tendon thickness and hypervascularity. Lastly, Barnes and colleagues completed a prospective study evaluating the use of the same percutaneous ultrasonic tenotomy procedure in 19 patients with either lateral or medial epicondylopathy. At 12 months following the procedure, the average improvement of the visual analog scale (VAS) and Disabilities of the Arm, Shoulder and Hand (DASH) assessment score maintained statistical significance when compared with baseline scores. The investigators reported no complications, and the average procedure time was less than 15 minutes.
A microdebrider coblation device has similarly been shown to achieve successful outcomes in treating lateral epicondylopathy. Meknas and colleagues carried out a prospective, randomized controlled trial in which 24 patients were randomized into 2 treatment groups: extensor tendon surgical release and repair and percutaneous tenotomy using the device. The patients in the tenotomy group had better outcomes than the surgery group with regard to VAS for pain and grip strength, which persisted for 18 months.
Autologous blood injection
The earliest study documenting this technique was performed by Edwards and Calandrucio where 28 patients who had failed other nonsurgical treatments (physical therapy, splinting, nonsteroidal antiinflammatory drugs [NSAIDs], and steroid injections) were injected at the point of maximum tenderness with 2 mL of autologous blood mixed with either 1 mL of 2% lidocaine HCL or 0.5% bupivacaine HCL. The patients were followed-up to an average of 9.5 months after their injection, and 79% of the patients experienced complete relief. Since this initial study, there have been several studies comparing ABI with other modalities. Chou and colleagues performed a meta-analysis of randomized controlled trials using ABI for lateral epicondylopathy and determined that ABI is more effective than corticosteroid injections (CSI) in reducing pain scores but not as effective as PRP in decreasing pain scores. Arirachakaran and colleagues performed a systematic review and network meta-analysis of PRP versus ABI versus CSI in the treatment of lateral epicondylitis and concluded that ABI may provide more improvement in pain VAS and DASH assessment when compared with CSI, but not when compared with PRP. In addition, ABI was shown to have a higher risk of complications versus the other 2 injections. Houck and colleagues completed a systematic review of overlapping meta-analysis of treatments of lateral epicondylopathy and reached similar conclusions to Arirachakaran and colleagues. Furthermore, they determined that the study performed by Arirachakaran and colleagues seemed to have the highest level of evidence.
One of the initial studies documenting PRP use in lateral epicondylopathy was performed by Mishra and Pavelko. They injected 20 patients (15 with PRP and 5 with anesthetic) who experienced lateral elbow pain for at least 3 months with a VAS score of 60 out of 100 or higher, in addition to failing conservative treatments, including home exercise program, bracing, NSAIDs, and steroid injection. The PRP group showed a 93% reduction in their pain score compared with baseline and 94% returned to sporting activities at an average follow-up of 25.6 months. Mishra and colleagues then conducted a double-blind randomized controlled trial where they compared the use of leukocyte-rich PRP to needle fenestration (with anesthetic) in 230 patients. A successful outcome was defined as a greater than 25% improvement from baseline on VAS with resisted wrist extension. At 24 weeks postprocedure 83.9% of PRP patients experienced successful outcome as compared with 68.3% of the needle fenestration group. Since these studies, there have been several investigations evaluating PRP utilization for this condition. , The aforementioned papers highlight the ability of PRP to produce long-term improvement when compared with steroid injections and without the complications of ABI. In addition, PRP has been shown to improve the architecture of the diseased tendon. This improvement in tendon architecture correlates with decrease pain and improved resisted wrist extension. Lastly, PRP for this condition has demonstrated the capacity to reduce the need for surgical intervention. Hastie and colleagues performed a retrospective review in which they looked at the need for arthroscopic release of the common extensor tendon 4 years before implementing PRP into their institution and compared it with that 4 years after implementing PRP. They found a statistically significant decrease in the number of patients requiring surgical intervention; the number of surgical patients went from 12.75 per year to 4.25 per year after including PRP in their treatment algorithm for lateral epicondylopathy.
Bone marrow aspirate concentrate
There is limited but favorable literature involving the use of bone marrow aspirate concentrate for elbow epicondylopathy. Moon and colleagues explored the use of BMAC injections of the common extensor or common flexor tendons following elbow arthroscopy for epicondylopathy. The outcomes of the study included VAS and Mayo elbow performance scores (MEPS) at 8 weeks and 6 months after the procedure and sonographic appearance of the tendon pre- and postprocedure. All patients showed improvement in their VAS, although not statistically significant. However, their improvement in their MEPS was shown to be statistically significant. In addition, all participants had normal-appearing tendon echotexture postprocedure. The second study evaluating BMAC injections for common extensor tendinopathy was performed by Singh and colleagues where 30 patients were injected. The main outcome was patient-rated tennis elbow evaluation score (PRTEE). They noted that the mean decrease in the PRTEE score was statistically significant at 2, 6, and 12 weeks. The investigators determined that BMAC injections were an effective treatment of common extensor tendinopathy in the short and medium term.
Currently only one published article exists dealing with the use of adipose MSC for the use for elbow epicondylopathy. Lee and colleagues injected 12 participants’ hypoechoic areas in the common extensor tendon with allogenic adipose-derived MSCs. Of the 12 patients, 6 patients received 10 6 cells in 1 mL, and the remaining 6 patients received an injection of 10 7 cells in 1 mL. All patients had their injections mixed with fibrinogen to create a fibrin matrix for the adipose tissue. These investigators evaluated the safety of the procedure by tracking adverse outcomes and the efficacy by measuring VAS, modified mayo elbow performance index (MEPI), and musculoskeletal ultrasound evaluation at 6, 12, 26, and 52 weeks postinjection. The investigators observed that the VAS progressively decreased over the entire postinjection period and the MEPI improved as well; however, both these outcomes plateaued after 6 weeks. No statistical difference in improvement of VAS or MEPS was found between the 2 groups. In addition, the investigators noted progressive decrease in the hypoechoic defect in both groups over the postprocedure period. Lastly, no significant adverse events were noted in either group.
Medial Epicondylopathy/Common Flexor Tendinopathy
This degenerative process is the second most common tendinopathy at the elbow. It occurs at the common flexor tendon originating from the medial epicondyle. It is 3- to 6-fold less common than lateral epicondylopathy; however, it has similar pathogenesis to its lateral elbow counterpart.
There are no studies exclusively evaluating the treatment of the common flexor tendon with this technique. However, it has been evaluated in conjunction with other elbow tendon pathologies. As mentioned previously, Barnes and colleagues evaluated the use of an ultrasound-guided percutaneous ultrasonic tenotomy procedure on common flexor and common extensor tendinopathy. Of the 19 patients evaluated, 7 of them had their common flexor tendon treated. There was a statistically significant improvement in VAS, MEPS, and DASH scores at 6 months and 12 months in all patients (medial and lateral epicondyle tendons); however, the investigators did not report the individual results for the common flexor and common extensor tendon patients. Boden and colleagues conducted a retrospective review of 62 patients who underwent either PRP or ultrasound-guided percutaneous ultrasonic tenotomy procedure performed for their elbow epicondylopathy, with 10 patients having medial epicondylopathy. The patients completed a postprocedure outcome survey with the primary outcomes being VAS, Quick DASH, and EuroQol-5D scores. PRP and ultrasound-guided percutaneous ultrasonic tenotomy procedure both demonstrated clinical and statistical improvement in the VAS, Quick DASH, and EuroQol-5D scores with an average follow-up of 10 months in the percutaneous ultrasonic tenotomy group and 17 months in the PRP group. There was no statistically significant difference between the 2 treatment groups. The investigators concluded that both techniques are effective, minimally invasive nonsurgical treatment options for medial and lateral epicondylopathy. Lastly, Stover and colleagues performed a retrospective chart review on 131 patients who underwent ultrasound-guided percutaneous tenotomy for common extensor, common flexor, or triceps tendinopathy. The outcomes measured included pain, quality of life, satisfaction with outcome, and complications at short-term (2 weeks, 6 weeks, and 12 weeks) and long-term (up to 4 years) follow-up. Of the 131 patients, 19 underwent treatment of their common flexor tendinopathy. In that group, pain decreased from 93% at baseline to 0% at long term follow-up. The common flexor group also demonstrated improvement in physical function and long-term follow-up, and there were no reported complications. The investigators concluded that the ultrasound-guided percutaneous tenotomy for elbow tendinopathies can reduce pain and improve physical function.
Autologous blood injection
Suresh and colleagues conducted a prospective study where 20 patients received needle fenestration and 2 ABI injections 4 weeks apart. The outcomes measured for the study were VAS score, modified Nirschl score, and sonographic changes in the tendon (hypoechoic changes, neovascularity, and interstitial tears) at 4 weeks and 10 months. Seventeen of the twenty patients had favorable outcomes. Of that cohort, their improvement in VAS at 4 weeks and 10 months was statistically significant. In addition, the decrease in modified Nirschl score was statistically significant at both times when compared with preprocedure scores. With regard to the sonographic changes, all 17 patients showed a decrease in their hypoechoic changes and neovascularity; however, only 11 of the 17 patients achieved complete resolution of their interstitial tears.
There are no studies exclusively evaluating PRP for medial epicondylopathy. The study with the largest number of patients to receive PRP for this issue was performed by Varshney and colleagues. This randomized control trial compared the use for PRP versus steroid injections for elbow epicondylopathy. Of the 83 patients in the analysis; 20 patients had medial epicondylopathy. Overall, the investigators concluded that PRP was superior to steroid injections at reducing pain and increasing elbow function starting at 6 months. However, there was no distinction made between lateral and medial epicondylopathy in the results.
Ulnar Collateral Ligament Injury
The full pathogenesis of this injury is discussed elsewhere in this issue. Briefly, ulnar collateral ligament (UCL) injuries occur from acute trauma including elbow dislocations or as an overuse injury resulting in the chronic degeneration of the ligament and eventual tears. The latter is a serious injury typically occurring in overhead athletes, particularly baseball pitchers. It occurs from repetitive valgus stress across the medial elbow, specifically, the anterior band of the medial UCL.
Several retrospective studies exist in the literature evaluating the use of PRP for UCL injuries with promising results. The first published study performed by Podesta and colleagues consisted of 34 patients receiving a single ultrasound-guided leukocyte-rich PRP injection ( Fig. 3 ) for MRI-confirmed UCL partial thickness tear followed by a specific postinjection rehabilitation protocol and interval throwing program. The outcomes for the study included return to play at 12 weeks, Kerlan-Jobe Othropedic Clinic Shoulder and Elbow questionnaire (KJOC), DASH, and dynamic ultrasound evaluation of humeral-ulnar joint space measurement with applied valgus stress. The improvement in postinjection KJOC, DASH, and dynamic ultrasound evaluation were all statistically significant with an average follow-up time of 70 weeks. Lastly, 30 of the 34 patients were able to return to their previous level of competition. Deal and colleagues conducted a retrospective study of 25 patients who received a PRP injection for this injury. In the study, all subjects’ physical examination findings were consistent with UCL insufficiency and MRI-confirmed grade 2 partial thickness injury. On MRI confirmation, patients were placed in a varus-forcing hinged elbow brace followed by 2 ultrasound-guided autologous nonactivated leukocyte-rich PRP injections spaced 2 weeks apart. Following the injections, the patients completed a supervised rehabilitation protocol and progressed to a return to throwing program when they were able to wean out of the hinged brace when they were pain free on examination. Four weeks after starting the postinjection protocol, a new MRI was performed to evaluate for the reconstitution of the ligament. All 25 patients showed reconstitution of the ligament with 20 of the athletes showing complete reconstitution. In addition, 96% of the athletes were able to return to the same or higher level of competition with an average return-to-competition time of 82 days.