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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.

Chronic kidney disease (CKD) is a common condition and leading cause of mortality in cats. Mesenchymal stromal cells (MSCs) may have a therapeutic effect on CKD. The aim of this pilot study was to determine efficacy of systemically-administered allogeneic uterine tissue-derived MSCs (UMSCs) in cats with CKD. Eighteen renal-compromised, unilaterally nephrectomized cats received two doses of 3 × 107 allogeneic UMSCs given intravenously (IV) with a 2-week dose interval. The primary endpoint was renal function, with treatment success defined by a 20% increase in glomerular filtration rate (GFR; iohexol clearance) and/or a 20% decrease in plasma creatinine in 50% of the cats. Secondary endpoints included diet and water consumption, body weight, urine characteristics, and adverse events. Treatment was well tolerated and associated with a statistically meaningful increase in GFR on Days 13, 28, 57, 99, 121 and 182, compared with baseline (P

The purpose of this study is to assess safety and feasibility of intradiscal bone marrow concentrate (BMC) injections to treat low back discogenic pain as an alternative to surgery with three year minimum follow-up. A total of 26 patients suffering from degenerative disc disease and candidates for spinal fusion or total disc replacement surgery were injected with 2 ml autologous BMC into the nucleus pulposus of treated lumbar discs. A sample aliquot of BMC was characterized by flow cytometry and CFU-F assay to determine progenitor cell content. Improvement in pain and disability scores and 12 month post-injection MRI were compared to patient demographics and BMC cellularity. After 36 months, only six patients progressed to surgery. The remaining 20 patients reported average ODI and VAS improvements from 56.7 ± 3.6 and 82.1 ± 2.6 at baseline to 17.5 ± 3.2 and 21.9 ± 4.4 after 36 months, respectively. One year MRI indicated 40% of patients improved one modified Pfirrmann grade and no patient worsened radiographically. Cellular analysis showed an average of 121 million total nucleated cells per ml, average CFU-F of 2713 per ml, and average CD34+ of 1.82 million per ml in the BMC. Patients with greater concentrations of CFU-F (>2000 per ml) and CD34+ cells (>2 million per ml) in BMC tended to have significantly better clinical improvement. There were no adverse events related to marrow aspiration or injection, and this study provides evidence of safety and feasibility of intradiscal BMC therapy. Patient improvement and satisfaction with this surgical alternative supports further study of the therapy.

Stem cells are being evaluated in numerous human clinical trials and are commercially used in veterinary medicine to treat horses and dogs. Stem cell differentiation, homing to disease sites, growth and cytokine factor modulation, and low antigenicity contribute to their therapeutic success. Bone marrow and adipose tissue are the two most common sources of adult-derived stem cells in animals. We report on the existence of an alternative source of primitive, multipotent stem cells from the equine umbilical cord cellular matrix (Wharton's jelly). Equine umbilical cord matrix (EUCM) cells can be cultured, cryogenically preserved, and differentiated into osteo-, adipo-, chondrogenic, and neuronal cell lineages. These results identify a source of stem cells that can be non-invasively collected at birth and stored for future use in that horse or used as donor cells for treating unrelated horses.

The purpose of this study is to assess safety and feasibility of intradiscal bone marrow concentrate (BMC) injections to treat discogenic pain as an alternative to surgery. A total of 26 patients (11 male, 15 female, aged 18–61 years, 13 single level, 13 two level) that met inclusion criteria of chronic (> 6 months) discogenic low back pain, degenerative disc pathology assessed by magnetic resonance imaging (MRI) with modified Pfirrmann grade of IV–VII at one or two levels, candidate for surgical intervention (failed conservative treatment and radiologic findings) and a visual analogue scale (VAS) pain score of 40 mm or more at initial visit. Initial Oswestry Disability Index (ODI) and VAS pain score average was 56.5 % and 80.1 mm (0–100), respectively. Adverse event reporting, ODI score, VAS pain score, MRI radiographic changes, progression to surgery and cellular analysis of BMC were noted. Retrospective cell analysis by flow cytometry and colony forming unit-fibroblast (CFU-F) assays were performed to characterise each patient’s BMC and compare with clinical outcomes. The BMC was injected into the nucleus pulposus of the symptomatic disc(s) under fluoroscopic guidance. Patients were evaluated clinically prior to treatment and at three, six, 12 and 24 months and radiographically prior to treatment and at 12 months. There were no complications from the percutaneous bone marrow aspiration or disc injection. Of 26 patients, 24 (92 %) avoided surgery through 12 months, while 21 (81 %) avoided surgery through two years. Of the 21 surviving patients, the average ODI and VAS scores were reduced to 19.9 and 27.0 at three months and sustained to 18.3 and 22.9 at 24 months, respectively (p ≤ 0.001). Twenty patients had follow-up MRI at 12 months, of whom eight had improved by at least one Pfirrmann grade, while none of the discs worsened. Total and rate of pain reduction were linked to mesenchymal stem cell concentration through 12 months. Only five of the 26 patients elected to undergo surgical intervention (fusion or artificial disc replacement) by the two year milestone. This study provides evidence of safety and feasibility in the non-surgical treatment of discogenic pain with autologous BMC, with durable pain relief (71 % VAS reduction) and ODI improvements (> 64 %) through two years.

Degenerative disc disease (DDD) induces chronic back pain with limited nonsurgical options. In this open label pilot study, 26 patients (median age 40 years; range 18–61) received autologous bone marrow concentrate (BMC) disc injections (13 one level, 13 two levels). Pretreatment Oswestry disability index (ODI) and visual analog scale (VAS) were performed to establish baseline pain scores (average 56.5 and 79.3, respectively), while magnetic resonance imaging was independently scored according to the modified Pfirrmann scale. Approximately 1 ml of BMC was analyzed for total nucleated cell (TNC) content, colony-forming unit-fibroblast (CFU-F) frequency, differentiation potential, and phenotype characterization. The average ODI and VAS scores were reduced to 22.8 and 29.2 at 3 months, 24.4 and 26.3 at 6 months, and 25.0 and 33.2 at 12 months, respectively (p ≤ .0001). Eight of twenty patients improved by one modified Pfirrmann grade at 1 year. The average BMC contained 121 × 106 TNC/ml with 2,713 CFU-F/ml (synonymous with mesenchymal stem cells). Although all subjects presented a substantial reduction in pain, patients receiving greater than 2,000 CFU-F/ml experienced a significantly faster and greater reduction in ODI and VAS. Subjects older than 40 years who received fewer than 2,000 CFU-F/ml experienced an average pain reduction of 33.7% (ODI) and 29.1% (VAS) at 12 months, while all other patients' average reduction was 69.5% (ODI, p = .03) and 70.6% (VAS, p = .01). This study provides evidence of safety and feasibility in the nonsurgical treatment of DDD with autologous BMC and indicates an effect of mesenchymal cell concentration on discogenic pain reduction. Stem Cells 2015;33:146–156

For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal stem cells (BMSCs) are regarded as a critical component of bone healing. However, the interactions of BMSCs and commercial bone matrices are poorly reported. BMSCs were cultured with several commercially available bone substrates (allograft, demineralized bone matrix (DBM), collagen, and various forms of calcium phosphates) for 48 h to understand their response to graft materials during surgical preparation and the first days following implantation (cell retention, gene expression, pH). At 30 and 60 min, bone chips and inorganic substrates supported significantly more cell retention than other materials, while collagen-containing materials became soluble and lost their structure. At 48 h, cells bound to β-tricalcium phosphate-hydroxyapatite (βTCP-HA) and porous hydroxyapatite (HA) granules exhibited osteogenic gene expression statistically similar to bone chips. Through 24 h, the DBM strip and βTCP-collagen became mildly acidic (pH 7.1–7.3), while the DBM poloxamer-putties demonstrated acidity (pH < 5) and the bioglass-containing carrier became basic (pH > 10). The dissolution of DBM and collagen led to a loss of cells, while excessive pH changes potentially diminish cell viability and metabolism. Extracts from DBM-poloxamers induced osteogenic gene expression at 48 h. This study highlights the role that biochemical and structural properties of biomaterials play in cellular function, potentially enhancing or diminishing the efficacy of the overall therapy.