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.

Atraumatic Medullary Osteonecrosis of the Tibia and Femur Treated With Intraosseous Orthobiologics.

Osteonecrosis (ON) is a painful condition involving bony cell death with resultant architectural collapse. This report discusses the case of a 50-year-old Caucasian female who presented to an outpatient musculoskeletal clinic with severe chronic left knee pain. She had a history of ulcerative colitis and resultant chronic corticosteroid exposure with subsequent development of knee ON. She was treated with an intraosseous autologous bone marrow concentrate (BMC), demineralized bone matrix (DBM), and platelet-rich plasma (PRP) injection. At 11 months post-injection, she demonstrated a significant improvement in pain scores, mobility, activity, and decreased narcotic use. Intraosseous orthobiologic injection for the treatment of knee ON is a promising procedure with a reasonable safety profile that warrants further study as an alternative to surgical intervention.

Risks of Intradiscal Orthobiologic Injections: A Review of the Literature and Case Series Presentation.

BACKGROUND: Intervertebral disc disease (IDD) is responsible for a large portion of back pain with historically suboptimal treatments for long-term improvement. IDD pathogenesis is thought to arise at a cellular and biochemical level, making biologically based injections an area of clinical interest. Although human studies have shown promise, emerging data suggest there may be risks inherent to such injections that were previously unrecognized. The aim of this review is to summarize the known risks to date and provide mitigation steps to reduce potential complications in the future. In addition, we present a small case series of serious adverse events (SAEs) from our clinical practice. METHODS: A literature review was performed to identify human intradiscal autologous biologic injection studies to date, including mesenchymal signaling cells (MSCs) and platelet-rich plasma (PRP) preparations, which were reviewed for complications. Cases of complication following intradiscal orthobiologic injection were identified from a single outpatient center and reviewed. RESULTS: Publications of MSC-based intradiscal injection documented 136 total patients treated with two SAEs reported, one infection and one progressive disc herniation. Publications of PRP intradiscal injection included 194 patients with one SAE reported. We also review three cases of previously unpublished SAEs, including one case of confirmed infection with Cutibacterium acnes (C acnes) and two presumed cases of discitis without pathogen confirmation. Bone marrow concentrate was the injectate in all three cases. CONCLUSIONS: Although biologic intradiscal injection shows promise for the treatment of discogenic back pain, there are inherent risks to be considered and mitigated. We currently recommend a leukocyte-rich PRP and a two-needle delivery technique coupled with intradiscal gentamicin to mitigate the risk of postinjection spondylodiscitis. Further research is needed using large registries to not only track clinical outcomes but also complication rates.

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.

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.

Intervention for Increasing Vitamin D Supplementation in a Deficient Rehabilitation Population: Outcomes of a Quality Improvement Initiative.

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent and increases the risk of osteoporosis, falls, and fractures. Patients in acute inpatient rehabilitation have several risk factors for VDD, the adverse effects of which may hinder long-term functional gain. OBJECTIVE: To evaluate the prevalence of and risk factors for VDD in patients admitted to acute inpatient rehabilitation and to evaluate the efficacy of a standardized vitamin D screening and supplementation protocol. DESIGN: Prospective cohort study as part of a quality improvement initiative. SETTING: An academic, freestanding acute inpatient rehabilitation hospital. PARTICIPANTS: Patients consecutively admitted over a 4-month period between November 2014 and February 2015 (n=128 pre-intervention and n=129 post-intervention). INTERVENTION: Universal screening of vitamin D level on admission followed by utilization of a standard supplementation protocol. MAIN OUTCOME MEASURES: Vitamin D insufficiency (VDI) and VDD prevalence along with screening, and supplementation rates. RESULTS: Preintervention, 10.2% of patients were screened for VDD, with 23.1% VDI and 46.2% VDD. Postintervention, 89.9% were screened, with 31.9% VDI and 47.4% VDD. 6.3% of all patients were supplemented on vitamin D preintervention compared to 53.5% postintervention. In multivariate analyses, the odds of VDD was significantly associated with African American race (OR 7.30, 95% CI, 1.56-34.20, P = .12) and age younger than 65 (OR 13.62 95% CI, 2.51-73.83, P = .002). Diagnoses in the "other neurologic" category were associated with decreased odds of VDD (OR 0.01, 95% CI, 0.001-0.193, P = .002). CONCLUSIONS: Given the high prevalence of VDD in an acute inpatient rehabilitation hospital, a routine screening and standardized supplementation protocol may improve quality of care. LEVEL OF EVIDENCE: III.

Platelet-rich plasma for the treatment of coccydynia: a case report and review of regenerative medicine for coccydynia.

Aim: To describe the successful treatment of coccydynia using ultrasound-guided injection of platelet-rich plasma. Setting: Outpatient orthopedic practice. Patient: 17-year-old female with BMI of 42.6. Case description: The patient presented with 6 months of nontraumatic coccygeal pain exacerbated by sitting. Physical exam was significant for point-tenderness over the sacral hiatus and coccyx. A corticosteroid injection around the sacrococcygeal ligament was administered with immediate resolution of her pain following the injection with the anesthetic. The patient reported significant pain relief for 1 week. The superficial sacrococcygeal ligament was then treated with a platelet-rich plasma injection under US guidance. Results: The patient reported a 70% improvement in pain and sitting tolerance at 6 weeks. By 6 months post injection, her pain was 100% resolved, and she remained pain free at the 12-month follow-up. Conclusion: Platelet-rich plasma may be considered as a treatment option in patients with refractory coccydynia.

Primary Cleft Lip and Palate Repair in Assam, India: Does Preoperative Anthropometric Analysis Help Identify Patients With Increased Surgical Risk in a Clinically Prescreened Population?

OBJECTIVE: To compare anthropometric z-scores with incidence of post-operative complications for patients undergoing primary cleft lip or palate repair. DESIGN: This was a retrospective observational analysis of patients from a surgical center in Assam, India, and includes a cohort from a single surgical mission completed before the opening of the center. SETTING: Patients included in the study underwent surgery during an Operation Smile mission before the opening of Operation Smile's Guwahati Comprehensive Cleft Care Center in Guwahati, India. The remaining cohort received treatment at the center. All patients received preoperative assessment and screening; surgery; and postoperative care, education, and follow-up. PATIENTS, PARTICIPANTS: Our sample size included 1941 patients and consisted of all patients with complete information in the database who returned for follow-up after receiving primary cleft lip repair or primary cleft palate repair between January 2011 and April 2013. INTERVENTIONS: Preoperative anthropometric measurements. MAIN OUTCOME MEASURE(S): Postoperative complications. RESULTS: Anthropometric z-scores were not a significant predictor of adverse surgical outcomes in the group analyzed. Palate surgery had increased risk of complication versus lip repair, with an overall odds ratio of 5.66 (P < .001) for all patients aged 3 to 228 months. CONCLUSIONS: Anthropometric z-scores were not correlated with increased risk of surgical complications, possibly because patients were well screened for malnutrition before surgery at this center. Primary palate repair is associated with an approximate fivefold increased risk of developing postoperative complication(s) compared with primary lip repair.

Surgical margin reporting in breast conserving surgery: Does compliance with guidelines affect re-excision and mastectomy rates?

PURPOSE: Margin status is important in guiding decisions to re-excise following breast-conserving surgery (BCS) for breast cancer. The College of American Pathologists (CAP) developed guidelines to standardize pathology reporting; however, compliance with margin documentation guidelines has been shown to vary. The aim of this retrospective study was to determine whether compliance with CAP guidelines affects re-excision and mastectomy rates. METHODS: We identified 1423 patients diagnosed with breast cancer between 1998 and 2006 who underwent BCS with negative margins. CAP compliance was categorized as maximal, minimal, or non-compliant. Statistical analyses were performed comparing the frequency of re-excision and mastectomy after initial BCS according to CAP margin reporting guideline compliance. Data were adjusted for provider facility by including a clustering variable within the regression model. RESULTS: Patients with non-compliant margin reporting were 1.7 times more likely to undergo re-excision and/or mastectomy than those with maximally compliant reporting. Level of compliance was most strongly associated with the frequency of mastectomy; non-compliant margin reporting was associated with a 2.5-fold increase in mastectomy rates compared to maximally compliant reporting. The results did not substantially change when the analyses accounted for clustering at the provider facility level. CONCLUSIONS: Our findings suggest that compliance with CAP guidelines in pathology reporting may be associated with variation in re-excision and mastectomy rates following BCS.