The rate of venous thromboembolism after knee bone marrow concentrate procedures: should we anticoagulate?

PURPOSE: Intra-articular injections of autologous, minimally manipulated, cell therapies such as bone marrow concentrate (BMC) to treat knee osteoarthritis (OA) may delay or prevent future total knee arthroplasty (TKA). Arthroplasty has the known and substantial risk of venous thromboembolism (VTE) and requires routine prophylaxis, whereas the VTE risk associated with knee BMC injections is unknown. We report on the rate of VTE from a large orthobiologics patient registry and assess whether knee BMC procedures require routine prophylaxis. METHODS: A retrospective analysis of knee osteoarthritis cases tracked in a treatment registry and treated at 72 clinical sites with BMC from 2007 to 2020 who were not prophylactically anticoagulated was performed to identify adverse events (AEs) associated with VTE. Treating physicians were contacted to improve discovery of possible occurrences of VTE. RESULTS: Twenty cases (0.16%) of VTE were identified from the registry of 12,780 knee BMC treatments. These events were less frequent than the published data demonstrate for anticoagulated TKA patients. CONCLUSION: Based on the rates of VTE from our retrospective treatment registry analysis compared to the risk of medication-induced haemorrhage, routine prophylactic anticoagulation is not recommended for intra-articular knee BMC procedures. Further research into safety and efficacy of BMC treatment for knee OA is warranted. CLINICAL TRIAL IDENTIFIER: NCT03011398, retrospectively registered.

Regenerative Injection Treatments Utilizing Platelet Products and Prolotherapy for Cervical Spine Pain: A Functional Spinal Unit Approach.

Background The increasing burden of musculoskeletal disorders combined with the high utilization of opiates and the relatively limited ability of traditional approaches to satisfactorily address many of these conditions has spurred an increased interest in alternative treatments such as regenerative medicine therapies. Evidence is growing to support the use of regenerative injection treatments, including prolotherapy, platelet-rich plasma (PRP), platelet lysate (PL), and mesenchymal stromal cells. This study aims to offer a proof of concept via a case series of patients with neck pain treated using a functional spinal unit (FSU) model with combination prolotherapy, PRP, and PL injections. Methodology A chart review identified patients with neck pain treated with a combination of cervical injections using concentrated platelets and prolotherapy. Results A total of 14 patients met the inclusion criteria. The average decrease in the Numeric Pain Score was 2.8 (p = 0.002). The mean decrease in the Functional Rating Index was 27.3 (p = 0.004) at 24 months. Two patients had mild adverse reactions. Conclusions This case series demonstrates basic safety and clinically significant improvements in patients treated for neck pain with autologous concentrated platelet products and prolotherapy utilizing an FSU treatment protocol. Additional clinical studies are warranted with a larger patient sample size and longer follow-up periods.

Use of Bone Marrow Concentrate to Treat Pain and Musculoskeletal Disorders: An Academic Delphi Investigation.

BACKGROUND: Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. OBJECTIVES: The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. STUDY DESIGN: Delphi panel technique. SETTING: The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. METHODS: An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. RESULTS: Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. LIMITATIONS: The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. CONCLUSIONS: There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.

The Treatment of Bone Marrow Lesions Associated with Advanced Knee Osteoarthritis: Comparing Intraosseous and Intraarticular Injections with Bone Marrow Concentrate and Platelet Products.

BACKGROUND: Bone marrow lesions are a radiographic indication of bony pathology closely associated with advanced osteoarthritis of the adjacent joint. Injection of autologous orthobiologic products, including bone marrow concentrate and platelet-rich plasma, have demonstrated safety and efficacy in treating both advanced osteoarthritis (via intraarticular injection) and associated bone marrow lesions (via intraosseous injection). The relative efficacy of intraarticular versus intraosseous injection of orthobiologics has not been evaluated at the present time. OBJECTIVES: The objective was to evaluate differences in orthobiologic bone marrow lesions treatment, either as a collateral result of intraarticular injection with bone marrow concentrate and platelet products alone, or intraosseous plus intraarticular injection as measured by patient reported outcomes. STUDY DESIGN: This study employed a prospective case-matched cohort design. SETTING: This study took place at a single outpatient interventional orthopedic pain clinic. METHODS: Using data from a prospective orthobiologic treatment registry of knee patients, a population of knee osteoarthritis with bone marrow lesions patients who had undergone only intraarticular knee injections of bone marrow concentrate and platelets (for symptomatic advanced osteoarthritis) were age, gender, and disease severity case-matched to a series of advanced osteoarthritis and bone marrow lesions patients who underwent intraosseous plus intraarticular injections. Self-reported patient outcomes for Numeric Pain Scale, International Knee Documentation Committee, lower extremity functional scale, and a modified single assessment numeric evaluation were compared between the 2 treatment groups. RESULTS: Eighty patients were included, 40 in each group. Although pain and functional outcome scores were significantly improved in both treatment groups, there was no statistically significant differences in patient reported outcomes based on the type of treatment. LIMITATIONS: There are several limitations to this study, including multiple providers performing the injections, varying onset of symptoms to treatment, and additional injections after their initial treatment, that were not controlled. In addition, increasing the sample size may be beneficial as well, particularly with the large bone marrow lesions group, which did suggest possible improvement with intraosseous plus intraarticular over the intraarticular, although was not statistically significant in our sample. Limited data availability for this cohort as well as some missing data are other limitations to consider. CONCLUSION: Treating knee bone marrow lesions with intraosseous bone marrow concentrate and platelet products did not affect patient reported outcomes.

A Randomized Controlled Trial of the Treatment of Rotator Cuff Tears with Bone Marrow Concentrate and Platelet Products Compared to Exercise Therapy: A Midterm Analysis.

Injectable regenerative therapies such as bone marrow concentrate (BMC) and platelet-rich plasma (PRP) may represent a safe alternative in the treatment of rotator cuff tears. This is a midterm review of a randomized, crossover trial comparing autologous BMC and platelet product injections versus exercise therapy in the treatment of partial and full-thickness supraspinatus tears. Patients enrolled into the study were between 18 and 65 years of age presenting to an outpatient orthopedic clinic with partial to full thickness, nonretracted supraspinatus tendon tears. Enrolled patients were randomized to either ultrasound-guided autologous BMC with PRP and platelet lysate (PL) percutaneous injection treatment or exercise therapy. Patients could cross over to BMC treatment after at least 3 months of exercise therapy. Patients completed the Disability of the Arm, Shoulder and Hand (DASH) scores as the primary outcome measure. Secondary outcomes included the numeric pain scale (NPS), a modified Single Assessment Numeric Evaluation (SANE), and a blinded MRI review. At this midterm review, results from 25 enrolled patients who have reached at least 12-month follow-up are presented. No serious adverse events were reported. Significant differences were seen in patient reported outcomes for the BMC treatment compared to exercise therapy at 3 and 6 months for pain, and for function and reported improvement (SANE) at 3 months (p < .05). Patients reported a mean 89% improvement at 24 months, with sustained functional gains and pain reduction. MRI review showed a size decrease of most tears post-BMC treatment. These findings suggest that ultrasound-guided BMC and platelet product injections are a safe and useful alternative to conservative exercise therapy of torn, nonretracted supraspinatus tendons. This trial is registered with NCT01788683.

Bone Marrow Concentrate (BMC) Therapy in Musculoskeletal Disorders: Evidence-Based Policy Position Statement of American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.

A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up.

BACKGROUND: Cell-based therapies have shown promise for the treatment of knee osteoarthritis (OA). The current study compared exercise therapy to autologous bone marrow concentrate (BMC) and platelet products for knee OA treatment. METHODS: Patients with symptomatic knee OA (N = 48) were randomized into either an exercise therapy control group or treatment group with injection of autologous BMC and platelet products. Patients in the control group could crossover to BMC treatment after 3 months. Clinical outcomes were documented at baseline and at 6-weeks, 3, 6, 12 and 24 months, including the Knee Society Score (KSS), Pain Visual Analogue Scale, Short Form-12 Scales (SF-12), and Lower Extremity Activity Scale (LEAS). RESULTS: All patients in the exercise group crossed over to receive BMC treatment after 3 months (N = 22 crossover). At 3 months, KSS-knee, SF-12 Physical, and LEAS improved significantly in the crossover group compared to exercise, similar to significant improvements on KSS-knee and LEAS for the treatment group (N = 26) compared to exercise group at 3 months. After BMC treatment, patients' clinical outcome scores (except SF-12 Mental Health), were significantly improved through the 2-year follow-up compared to baseline. No serious adverse events were reported. CONCLUSION: The use of image-guided percutaneous BMC with platelet products yielded better results than exercise therapy as an effective alternative therapy for patients with symptomatic moderate to moderate-severe osteoarthritis of the knee. Trial registration NCT02034032. https://clinicaltrials.gov/ct2/show/NCT02034032 . Registered 13 January 2014.

Symptomatic anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow concentrate and platelet products: a non-controlled registry study.

BACKGROUND: Bone marrow concentrate (BMC) has shown promise in the treatment of several orthopedic conditions. This registry study investigated the use of autologous BMC and platelet products for percutaneous anterior cruciate ligament (ACL) treatment. METHODS: Twenty-nine patients presenting to a single outpatient interventional musculoskeletal and pain practice with symptomatic grade 1, 2, or 3 ACL tears with less than 1 cm retraction were enrolled. Patients were treated with a percutaneous ACL injection of autologous BMC and platelet products using fluoroscopic guidance. Pre- and post-treatment magnetic resonance imaging analysis was completed for 23 patients using ImageJ software for an objective quantitative analysis of pixel density as a proxy for ACL integrity. Subjective clinical outcome measures collected pre-treatment and at 1, 3, 6, 12, 18, 24, and 36 months post-treatment include the Numerical Pain Scale (NPS), the Lower Extremity Functional Scale (LEFS), the International Knee Documentation Committee (IKDC) form, and a modified version of the Single Assessment Numeric Evaluation. RESULTS: Seventy-seven percent of patients treated with BMC injections into the ACL showed significant improvement (p < 0.01) in objective measures of ACL integrity at an average of 8.8 months (median 4.7 months). The mean of last patient-reported improvement was 72% (SD = 35) at an average of 23 (SD = 10) months post-treatment. Mean scores were found to be significantly different (p < 0.05) for the NPS at 6, 18, and 24 months, and LEFS and IKDC at all time points (i.e. 1, 3, 6, 12, 18, 24, and 36 months) relative to baseline. CONCLUSION: In symptomatic patients with grade 1, 2, or even grade 3 tears with minimal retraction, ACL treatment with percutaneous injection of BMC and platelet products shows promise as a non-surgical alternative. However, a larger randomized controlled trial is warranted to confirm these findings. Trial registration NCT03011398. A Clinical Registry of Orthobiologics Procedures. https://clinicaltrials.gov/ct2/show/NCT03011398?term=orthobiologics&rank=1 . Registered 29 December 2016. Enrollment 1 December 2011-retrospectively registered.

The use of lumbar epidural injection of platelet lysate for treatment of radicular pain.

BACKGROUND: Epidural steroid injections (ESI) are the most common pain management procedure performed in the US, however evidence of efficacy is limited. In addition, there is early evidence that the high dose of corticosteroids used can have systemic side effects. We describe the results of a case series evaluating the use of platelet lysate (PL) epidural injections for the treatment of lumbar radicular pain as an alternative to corticosteroids. METHODS: Registry data was obtained for patients (N = 470) treated with PL epidural injections presenting with symptoms of lumbar radicular pain and MRI findings that were consistent with symptoms. Collected outcomes included numeric pain score (NPS), functional rating index (FRI), and a modified single assessment numeric evaluation (SANE) rating. RESULTS: Patients treated with PL epidurals reported significantly lower (p < .0001) NPS and FRI change scores at all time points compared to baseline. Post-treatment FRI change score means exceeded the minimal clinically important difference beyond 1 month. Average modified SANE ratings showed 49.7% improvement at 24 months post-treatment. Twenty-nine (6.3%) patients reported mild adverse events related to treatment. CONCLUSION: Patients treated with PL epidurals reported significant improvements in pain, exceeded the minimal clinically important difference (MCID) for FRI, and reported subjective improvement through 2-year follow-up. PL may be a promising substitute for corticosteroid.

Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy.

BACKGROUND: Degenerative disc disease (DDD) is a common cause of lower back pain with radicular symptoms and has a significant socioeconomic impact given the associated disability. Limited effective conservative therapeutic options result in many turning to surgical alternatives for management, which vary in the rate of success and also carry an increased risk of morbidity and mortality associated with the procedures. Several animal based studies and a few human pilot studies have demonstrated safety and suggest efficacy in the treatment of DDD with mesenchymal stem cells (MSCs). The use of bone marrow-derived MSCs for the treatment of DDD is promising and in the present study we report on the safety and efficacy findings from a registry based proof of concept study using a percutaneous intradiscal injection of cultured MSCs for the management of DDD with associated radicular symptoms. METHODS: Thirty-three patients with lower back pain and disc degeneration with a posterior disc bulge diagnosed on magnetic resonance imaging (MRI) met the inclusion criteria and were treated with culture-expanded, autologous, bone marrow-derived MSCs. Prospective registry data was obtained at multiple time intervals up to 6 years post-treatment. Collected outcomes included numeric pain score (NPS), a modified single assessment numeric evaluation (SANE) rating, functional rating index (FRI), measurement of the intervertebral disc posterior dimension, and adverse events. RESULTS: Three patients reported pain related to procedure that resolved. There were no serious adverse events (i.e. death, infection, or tumor) associated with the procedure. NPS change scores relative to baseline were significant at 3, 36, 48, 60, and 72 months post-treatment. The average modified SANE ratings showed a mean improvement of 60% at 3 years post-treatment. FRI post-treatment change score averages exceeded the minimal clinically important difference at all time points except 12 months. Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment. CONCLUSIONS: Patients treated with autologous cultured MSCs for lower back pain with radicular symptoms in the setting of DDD reported minor adverse events and significant improvements in pain, function, and overall subjective improvement through 6 years of follow-up. NCT03011398. A Clinical Registry of Orthobiologics Procedures. https://clinicaltrials.gov/ct2/show/NCT03011398?term=orthobiologics&rank=1.