To evaluate whether intraosseous (IO) autologous bone marrow concentrate (BMC), containing mesenchymal stem cells (MSCs) enumerated in vitro as colony forming unit-fibroblasts (CFU‑F), reduces or delays conversion to total hip arthroplasty (THA) compared with matched conservative care, and to assess the influence of disease progression and CFU‑F dose on outcomes. A monocentric matched cohort (n = 434 hips; 217 BMC, 217 control) was followed for up to 15 years. Bone marrow was aspirated from the iliac crest, processed into BMC to concentrate nucleated cells, and injected intraosseously into the femoral head under fluoroscopy. Demographics, BMI, osteoarthritis grade, and CFU‑F were recorded. The primary outcome was THA‑free survival by Kaplan–Meier with log‑rank testing. Cox proportional-hazard models provided adjusted effects and predictions. Progression to THA after 15 years occurred in 16.1

To compare platelet-rich plasma (PRP) with hyaluronic acid (HA), corticosteroid (CS), or saline placebo (NS) for symptomatic knee osteoarthritis (OA) and to assess whether total blood-draw volume, a proxy for platelet dose, is associated with treatment effect. Following PRISMA, randomized controlled trials comparing intra-articular PRP with HA, CS, or NS were identified. Random-effects meta-analyses estimated mean differences (MDs) in pain (VAS) and function (WOMAC) at six and twelve months. Risk of bias was assessed with RoB 2.0 and certainty of evidence with GRADE. Subgroup analyses stratified PRP vs HA trials by total blood draw volume (< 40 mL vs ≥ 40 mL). Sixty-two trials (n = 4,969) were included. PRP improved VAS and WOMAC versus HA, CS, and NS at six months and remained superior versus HA and CS at twelve months (insufficient studies for twelve-month PRP vs NS). In PRP vs HA trials, blood draw volume ≥ 40 mL was associated with larger improvements in six-month WOMAC (P = 0.004) and twelve-month VAS (P = 0.029). Heterogeneity was substantial (I2 > 90

Orthobiologic injections including platelet-rich plasma (PRP) and cell-based injections are becoming increasingly popular. Evidence suggests that these therapies can be effective in certain situations. The efficacy of these injections may be more dependent on the quality of the injectate, which given their autologous nature, may be dependent on lifestyle choices like exercise, diet, and supplements. The literature describing PRP injections shows that the number and activity of platelets can improve their efficacy. A multitude of lifestyle modifications can affect those factors. Exercise intensity appears to increase platelet count and increases adhesion as well as release of growth factors. Low inflammatory diets increase platelet counts and activity overall. Stress, some supplements, high cholesterol, or processed sugar diets can increase inflammation and potentially decrease platelet counts as well as quality of PRP injectate. Similarly, cell-based therapies can be affected by mesenchymal stromal cell (MSC) number and quality. Cell-based therapy is based upon limiting cellular senescence and increasing replication and differentiation. Exercise may limit senescence and improve replication and differentiation of these cell-based therapies, especially in older adult populations. There are a multitude of supplements that may potentiate these types of injections and patients should discuss the potential benefits and concerns when starting a supplement regimen. Certain foods as well as changes in oxygenation may limit cellular senescence and lower calorie intake may affect MSC viability and function as well. Overall, the current state of literature describes biologic plausibility of how exercise, diet and supplements might affect orthobiologic injection efficacy. Further translational research needs to be completed to describe the effect size and improve recommendations for clinical implementation.

Autologous bone marrow concentrate (BMC), platelet-rich plasma (PRP), and platelet lysate (PL) have emerged as promising orthobiologic treatment options for knee osteoarthritis (OA). The present observational study reports minimal clinically important difference (MCID) and substantial clinical benefit (SCB) values for several patient-reported outcome measures (PROMs) used to monitor changes in joint pain and function following percutaneous treatment of knee OA with a combination of BMC and platelet products (n = 295 knees). Distribution-based approaches were used to determine 12-month MCID values for the International Knee Documentation Committee (IKDC) subjective, Lower Extremity Functional Scale (LEFS), Numeric Pain Scale (NPS), and modified Single Assessment Numeric Evaluation (SANE) scores. Alternatively, a within-cohort, anchor-based approach, leveraging the modified SANE as a global transition question, was used to determine MCID values of 12.2, 8.4, and − 1.8, and SCB values of 29.5, 22.5, and − 3.0 for IKDC, LEFS, and NPS, respectively. Approximately 87% of treated knees reported change scores that met or exceeded an MCID value while 59% reported change scores that met or exceeded an SBC value for one or more PROMs. In reporting MCID and SCB values for PROMs following the treatment of knee OA with a combination of BMC and platelet products, we sought to provide a foundation for assessing the clinical efficacy of orthobiologic interventions in this developing field.

Anterior cruciate ligament (ACL) reconstruction (ACLR) surgery remains the prevailing standard of care for complete ACL ruptures but is not without risk. The aim of this study was to compare non-surgical, autologous bone marrow concentrate (BMC) with platelet products compared to exercise therapy for partial and complete, non-retracted ACL tears without meniscus injuries. In this randomized-controlled, crossover trial, patients received either exercise therapy or an injection of BMC with platelet products to treat ACL tears. After 3 months, if patients randomized to the exercise group were not satisfied with their improvement, they could crossover to receive the BMC treatment. Patients reported outcomes were completed at pre-treatment, 1-, 3, 6-, 12-, and 24-months of the Numeric Pain Scale (NPS), the International Knee Documentation Committee (IKDC) subjective knee form, Lower Extremity Function Scale (LEFS), and a modified Single Assessment Numeric Evaluation (SANE). MRIs at pre- and post-treatment were assessed using ImageJ software analysis. Complications and surgeries were assessed at each time point. Patients in the BMC group reported significantly greater change scores (from pre-treatment) on LEFS (P = 0.027), and SANE (P = 0.007) at 3 months compared to the exercise group. No significant differences were found between baseline and/or 1- month and 3-month follow-ups for any outcome measure (P > 0.05) in the exercise therapy group. When followed through 2 years, patients who received BMC treatment demonstrated sustained improvements in function and decreases in pain, with patients reporting a median of subjective improvement (SANE) of 90

Purpose:Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial. Methods:The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of "disagree" or "abstain", they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved. Results:Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies. Conclusion:In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose-response associations, and comparative analysis between different injectable biologics.

Abstract Background Surgical repair is recommended for the treatment of high-grade partial and full thickness rotator cuff tears, although evidence shows surgery is not necessarily superior to non-surgical therapy. The purpose of this study was to compare percutaneous orthobiologic treatment to a home exercise therapy program for supraspinatus tears. Methods In this randomized-controlled, crossover design, participants with a torn supraspinatus tendon received either ‘BMC treatment’, consisting of a combination of autologous bone marrow concentrate (BMC) and platelet products, or underwent a home exercise therapy program. After three months, patients randomized to exercise therapy could crossover to receive BMC treatment if not satisfied with shoulder progression. Patient-reported outcomes of Numeric Pain Scale (NPS), Disabilities of the Arm, Shoulder, and Hand, (DASH), and a modified Single Assessment Numeric Evaluation (SANE) were collected at 1, 3, 6, 12, and 24 months. Pre- and post-treatment MRI were assessed using the Snyder Classification system. Results Fifty-one patients were enrolled and randomized to the BMC treatment group (n = 34) or the exercise therapy group (n = 17). Significantly greater improvement in median ΔDASH, ΔNPS, and SANE scores were reported by the BMC treatment group compared to the exercise therapy group (-11.7 vs -3.8, P = 0.01; -2.0 vs 0.5, P = 0.004; and 50.0 vs 0.0, P < 0.001; respectively) after three months. Patient-reported outcomes continued to progress through the study’s two-year follow-up period without a serious adverse event. Of patients with both pre- and post-treatment MRIs, a majority (73%) showed evidence of healing post-BMC treatment. Conclusions Patients reported significantly greater changes in function, pain, and overall improvement following BMC treatment compared to exercise therapy for high grade partial and full thickness supraspinatus tears. Trial registration This protocol was registered with www.clinicaltrials.gov (NCT01788683; 11/02/2013).

Readily available and effective therapeutic approaches are increasingly required to overcome the growing demand for optimized management of musculoskeletal degenerative conditions. The use of biologic therapies has been gaining ground in the orthopedic field by showing promising results. In order to review the current status of orthobiologics and to discuss the potential risks, benefits, and challenges of their implementation, a recent expert conference hosted by the C. Wayne McIlwraith Translational Medicine Institute (TMI), and funded by the Dorothy Havemeyer Foundation was held at Colorado State University, in conjunction with the official Opening of the TMI. This review summarizes the conference findings highlighting the scientific challenges, safety concerns, and translation of orthobiologics to clinical practice.

Knee osteoarthritis (OA) is a common, progressively debilitating joint disease, and the intra-articular injection of autologous bone marrow concentrate (BMC) may offer a minimally invasive method of harnessing the body’s own connective tissue progenitor cells to counteract accompanying degenerative effects of the disease. However, the extent to which the progenitor cell content of BMC influences treatment outcomes is unclear. We sought to determine whether patient-reported outcome measures associated with BMC treatment for knee OA are related to the concentration of progenitor cells provided. In the present study, 65 patients (72 knees) underwent treatment for knee OA with autologous BMC and self-reported their outcomes for up to one year using follow-up questionnaires tracking function, pain, and percent improvement. A small fraction of each patient’s BMC sample was reserved for quantification with a haematological analyzer and cryopreserved for subsequent analysis of potential connective tissue progenitor cells using a colony-forming unit fibroblast (CFU-F) assay. Patients reported significant increases in function and overall percent improvement in addition to decreases in pain relative to baseline levels following treatment with autologous BMC that persisted through 12 months. Patients reporting improved outcomes (46 of 72 knees) received BMC injections having higher CFU-F concentrations than non-responding patients (21.1×103 ± 12.4×103 vs 14.3×103 ± 7.0 x103 CFU-F per mL). A progenitor cell concentration of 18×103 CFU-F per mL of BMC was found to best differentiate responders from non-responders. This study provides supportive evidence for using autologous BMC in the minimally invasive treatment of knee OA and suggests that increased progenitor cell content leads to improved treatment outcomes. ClinicalTrials.gov Identifier: NCT03011398, 1/7/17

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. 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. 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. 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. NCT03011398, retrospectively registered.

Background: There has been a recent emergence in the use of orthobiologics, including platelet-rich plasma (PRP) and bone marrow concentrate (BMC), in the treatment of various musculoskeletal conditions. The goal of this study was to determine if injection of BMC and platelet products into partial and full-thickness anterior cruciate ligament (ACL) tears can facilitate primary ligament healing in patients failing conservative care, resulting in improved outcomes compared to exercise therapy.Methods: Patients were randomized to either exercise therapy or percutaneous injection of autologous BMC with PRP and platelet lysate into the ACL under fluoroscopic guidance. Pain and function were assessed at baseline and at 1, 3, 6, 12, and 24 months. Baseline and 6-month post-treatment magnetic resonance imaging (MRI) were obtained to evaluate interval healing. Laxity was assessed using the Telos device.Results: There was significant improvement in functional outcomes in the BMC group, compared to base-line for LEFS at time points 3 up to 24 months s = 0.000000005), and significant improvement in pain in the BMC group at 6 (p = 0.00054), 12 (p = 0.00127), and 24 months (p = 0.002). There was no significant improvement in pain or function at any time point in the exercise therapy group. There was significant improvement in ACL MRI ImageJ quantitative assessment in the BMC group (p = 0.001) and no difference in the exercise group (p > 0.05). No serious adverse events were reported.Conclusion: Autologous BMC and platelet product injection into ACL tears improved patient function compared to exercise, observed through 24 months. Patients treated with BMC demonstrated quantitative improvements in post-treatment MRI scans suggestive of interval ligament healing.

BACKGROUNDBone 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.OBJECTIVESThe 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 DESIGNThis study employed a prospective case-matched cohort design.SETTINGThis study took place at a single outpatient interventional orthopedic pain clinic.METHODSUsing 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.RESULTSEighty 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.LIMITATIONSThere 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.CONCLUSIONTreating knee bone marrow lesions with intraosseous bone marrow concentrate and platelet products did not affect patient reported outcomes.

Background: Umbilical cord (UC) connective tissues contain plastic-adherent, colony forming unit–fibroblasts (CFU-Fs) amenable to culture expansion for potential therapeutic use. Recently, UC-derived allograft products have been made available to practitioners in orthopaedics and other specialties, by companies purporting “stem cell”–based healing. However, such marketing claims conflict with existing regulations for these human tissues, generating questions over the cellular and protein composition of current commercially available UC allograft products. Purpose: To evaluate commercial UC allograft products for viable cells, CFU-Fs, and protein makeup. Study Design: Descriptive laboratory study. Methods: Five commercial UC allograft products claiming to contain viable, undescribed “stem cells,” 2 obtained from UC blood (UCB) and 3 from UC tissue (UCT), were analyzed. Image-based methods were used to measure cell concentration and viability, a traditional CFU-F assay was used to evaluate in vitro behavior indicative of a connective tissue progenitor cell phenotype often referred to as mesenchymal stem/stromal cells, and quantitative immunoassay arrays were used to measure a combination of cytokines and growth factors. Bone marrow concentrate (BMC) and plasma derived from the blood and bone marrow of middle-aged individuals served as comparative controls for cell culture and protein analyses, respectively. Results: Viable cells were identified within all 5 UC allograft products, with those derived from UCB having greater percentages of living cells (40%-59%) than those from UCT (1%-22%). Compared with autologous BMC (>95% viability and >300 million living cells), no CFU-Fs were observed within any UC allograft product (<15 million living cells). Moreover, a substantial number of proteins, particularly those within UCB allograft products, were undetectable or present at lower concentrations compared with blood and bone marrow plasma controls. Interestingly, several important growth factors and cytokines, including basic fibroblast growth factor, hepatocyte growth factor, interleukin-1 receptor antagonist, and osteoprotegerin, were most prevalent in 1 or more UCT allograft products as compared with blood and bone marrow plasma. Conclusion: CFU-Fs, often referred to as stem cells, were not found within any of the commercial UC allograft products analyzed, and clinicians should remain wary of marketing claims stating otherwise. Clinical Relevance: Any therapeutic benefit of current UC allograft products in orthopaedic medicine is more likely to be attributed to their protein composition (UCT > UCB) or inclusion of cells without colony forming potential (UCB > UCT).

Centeno, Christopher J. MDa; Murrell, William MDb,c; Buford, Don MDd; Malanga, Gerard MDe,f; Freeman, Michael MedDr, PhDg,h; Mautner, Ken MDi; Money, Brandon DOa Author Information

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.

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.

Purpose: The prevalence of connective tissue progenitor cells within a cell-based therapy is often quantified using the colony-forming unit fibroblast (CFU-F) assay. The present study investigates the feasibility of using cryopreserved bone marrow aspirate concentrate (BMAC) as an alternative cell source to fresh BMAC for CFU-F quantification. Methods: Freshly prepared and corresponding cryopreserved BMAC samples from patients receiving autologous cell therapy (n = 98) were analyzed using the CFU-F assay for comparison. Cultures were established by directly plating BMAC at low cell densities and maintained for a 2-week growth period. Colonies were enumerated to determine CFU-F frequency, and a subset of cultures was imaged and analyzed to quantify colony area and density. Results: A nonlinear relationship was observed between plating density and CFU-F frequency over a wide range in plating densities (similar to 30-fold). Cryopreserved BMAC yielded recoverable (77 +/- 23%) and viable (73 +/- 9%) nucleated cells upon thawing. After cryopreservation, CFU-F frequencies were found to be significantly lower (56.6 +/- 34.8 vs. 50.3 +/- 31.7 colonies per million nucleated cells). Yet the number of CFU-F in fresh and cryopreserved BMAC were strongly correlated (r = 0.87) and had similar area and densities. Further, moderate correlations were observed between the number of CFU-F and nucleated cells, and both the mean colony area and density were negatively correlated with patient age. Notably, no relationship was found between CFU-F frequency and age, regardless of whether fresh or cryopreserved BMAC was used. Conclusions: Freshly prepared and cryopreserved BMAC yielded correlated results when analyzed using the CFU-F assay. Our findings support the cryogenic storage of patient BMAC samples for retrospective CFU-F analyses, offering a potential alternative for characterizing BMAC and furthering our understanding of progenitor cells in relation to clinical outcome. (c) 2020 International Society for Cell and Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Interventional orthobiologics is changing the landscape of orthopedic medicine. Various methods exist for treatment of many different musculoskeletal pathologies. Candidacy for such injections remains a debated topic, and current research is underway for stratifying the patients that would be most successful for certain techniques. Described in this commentary are the various methods of interventional orthobiologic techniques available such as: prolotherapy, platelet rich plasma (PRP), mesenchymal stromal cells (MSCs), culture-expanded MSCs and amniotic-based products. Here we review the healing cascade and how this relates to the application of the various injectates and rehabilitation protocols. In conclusion, there exists orthobiologic techniques for the healing of a multitude of musculoskeletal ailments, from ligamentous instabilities/tears, tendon derangements and osteoarthritis, however candidacy grades continue to be an area for discussion as to which type of treatment is the most beneficial, and which rehabilitation protocols are required. More randomized controlled trials and comparative analyses are needed for direct correlative conclusions for which interventional orthobiologic treatment and rehabilitation protocol is best after each respective treatment. Level of Evidence 5.

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. 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.

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.