Evidence-Based Clinical Practice Guidelines on Regenerative Medicine Treatment for Chronic Pain: A Consensus Report from a Multispecialty Working Group.

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.

Evaluation of Platelet-rich Plasma and Microneedling for Facial Skin Rejuvenation.

Background: The regenerative properties of platelet growth factors make platelet-rich-plasma (PRP) an attractive modality for treatment of aging skin. The main objective of this study was to determine efficacy and safety of PRP injections and microneedling compared with saline injections in women with aging skin of the face. Methods: In this prospective, randomized clinical trial, 18 women with facial aging were randomized to receive either PRP injections to the unilateral face and saline injections to the contralateral side, or vice versa. Microneedling was performed after injections on the entire face. Physician assessment, photographs, and treatment satisfaction questionnaires were used for outcome assessment at baseline and 16- and 24-week follow-ups. Results: There was no evidence of improvement and suggestion of worsening in skin laxity and rhytides from baseline to weeks 4, 16, and 24 for PRP and saline (all P ≤ 0.004) and no notable difference in skin roughness between baseline and follow-up time points for PRP or saline (all P ≥ 0.19). The degree of change in skin laxity, rhytides, and skin roughness from baseline to follow-up time points was similar for PRP and saline. All patients experienced some degree of pain/discomfort and burning/stinging sensation at treatment weeks 4, 8, and 12 for both saline and PRP. Conclusions: PRP injections did not seem to be effective for treatment of aging skin of the face in women, with no notable macroscopic improvement in appearance when compared with baseline or saline injections. Advanced age of study participants (>45 years) and less-sensitive methods of evaluation may be potential contributing factors to the lack of detected response.

Experts Achieve Consensus on a Majority of Statements Regarding Platelet-Rich Plasma Treatments for Treatment of Musculoskeletal Pathology.

PURPOSE: To establish consensus statements on platelet-rich plasma (PRP) for the treatment of musculoskeletal pathologies. METHODS: A consensus process on the treatment of PRP using a modified Delphi technique was conducted. Thirty-five orthopaedic surgeons and sports medicine physicians participated in these consensus statements on PRP. The participants were composed of representatives of the Biologic Association, representing 9 international orthopaedic and musculoskeletal professional societies invited due to their active interest in the study of orthobiologics. Consensus was defined as achieving 80% to 89% agreement, strong consensus was defined as 90% to 99% agreement, and unanimous consensus was indicated by 100% agreement with a proposed statement. RESULTS: There was consensus on 62% of statements about PRP. CONCLUSIONS: (1) PRP should be classified based on platelet count, leukocyte count, red blood count, activation method, and pure-plasma versus fibrin matrix; (2) PRP characteristics for reporting in research studies are platelet count, leukocyte count, neutrophil count, red blood cell count, total volume, the volume of injection, delivery method, and the number of injections; (3) the prognostic factors for those undergoing PRP injections are age, body mass index, severity/grade of pathology, chronicity of pathology, prior injections and response, primary diagnosis (primary vs postsurgery vs post-trauma vs psoriatic), comorbidities, and smoking; (4) regarding age and body mass index, there is no minimum or maximum, but clinical judgment should be used at extremes of either; (5) the ideal dose of PRP is undetermined; and (6) the minimal volume required is unclear and may depend on the pathology. LEVEL OF EVIDENCE: Level V, expert opinion.

Ultrasound-guided injection of the long head of the biceps tendon sheath with concomitant subacromial bursa injection through the same needlestick.

Sonography and specific shoulder positions allow for injections into both the long head of the biceps tendon sheath (LHBTS) and the subacromial space (SS) with one needlestick. We validated this technique using cadavers. An experienced proceduralist injected latex solution into 12 unembalmed cadaveric shoulders, aiming for the LHBTS and SS, using an ultrasound-guided injection technique that employs a single-needle entry point. An experienced surgeon dissected each specimen and graded latex location as: (1) completely accurate (in both the SS and LHBTS); (2) partially accurate (in either the SS or LHBTS); (3) accurate with overflow (in both locations, but also elsewhere); (4) partially accurate with overflow (in either location, but also somewhere else); or (5) completely inaccurate (no latex in either location). All 12 ultrasound-guided injections using the technique accurately placed latex into both LHBTS and SS (100% accuracy). Latex was also found in adjacent regions after two (17%) injections: one within the shoulder joint and one within the deltoid musculature. This newly described technique allows highly accurate access to the LHBTS and SS with single-needle entry. This technique could become a favored alternative to subjecting patients to two needlesticks and preparing separate injections to address often concomitant pathologies.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Effect of Bone Marrow Aspirate Concentrate and Platelet-Rich Plasma Augmentation on the Rate of Revision Rotator Cuff Repair.

Background: The application of orthobiologics at the time of arthroscopic rotator cuff repair (RCR) has received an increasing amount of clinical interest despite a relative scarcity of human clinical studies on their efficacy. Purpose: To utilize a national administrative database to determine the association of bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) applied at the time of RCR with revision surgery rates. Study Design: Cohort study; Level of evidence, 3. Methods: The Mariner data set from the PearlDiver patient records repository was utilized to identify patients undergoing RCR using Current Procedural Terminology (CPT) code 29827. Patients receiving BMAC or PRP at the time of RCR were then identified using CPT coding. For comparison purposes, a matched cohort was created consisting of patients who underwent RCR without biologic augmentation in a 5:1 fashion for each biologic separately. Cases were matched according to age, sex, tobacco use, biceps tenodesis, distal clavicle excision, and subacromial decompression. All groups were then queried for revision RCR or conversion to reverse shoulder arthroplasty. Revision rates were compared utilizing a multivariate binomial logistic regression analysis. Adjusted odds ratios (ORs) and 95% CIs were calculated. Results: A total of 760 patients who underwent biologic augmentation during RCR were identified, including 646 patients in the PRP group and 114 patients in the BMAC group. They were compared with 3800 matched controls without documented biologic application at the time of surgery. Compared with matched controls, patients who received BMAC at the time of surgery experienced a significantly lower incidence of revision surgery at 2 years (OR, 0.36; 95% CI, 0.15-0.82; P = .015). There was no significant difference in revision rates between PRP and matched controls (OR, 0.87; 95% CI, 0.62-1.23; P = .183). Conclusion: The application of BMAC at the time of RCR was associated with a significant decrease in the incidence of revision surgery. There was no apparent effect of PRP on the incidence of revision surgery after primary RCR. Higher-level clinical studies considering surgical factors are needed to more clearly define the role of biologic adjuvants in RCR.

The Direct to Consumer Stem Cell Market and the Role of Primary Care Providers in Correcting Misinformation.

INTRODUCTION: Direct to consumer stem cell and regenerative interventions (SCRIs) for various medical conditions have increased in popularity due to unmet medical needs and the promise of SCRIs to meet those needs. These interventions may have varying levels of safety and efficacy data and many lack sufficient scientific data to be marketed. The direct to consumer SCRI industry has received significant attention due to potential physical, economic, and emotional harms to patients. Patients may seek the counsel of their primary care providers when considering stem cell therapy for their condition. METHODS: Here we describe strategies primary care providers can utilize when counseling patients. RESULTS: Although we recommend constructing these discussions around individual patients' needs, one can utilize a general approach consisting of 4 parts. First, providers should recognize what information the patient is seeking and what is their understanding of stem cell and regenerative medicine. Next, providers should convey evidence-based information at the level of patients understanding so that they are aware of the risks, benefits, and descriptions of possible procedures. Throughout the conversations, attempts should be made to guide patients to a trusted resource that can provide additional information. Finally, providers should make an effort to address misinformation in a way that is nonjudgmental and patient-centered to make the patient feel safe and comfortable. CONCLUSION: Effectively communicating risk information by primary care providers to patients is important given the harms reported from direct-to-consumer SCRIs. Correcting misinformation remains a priority when discussing SCRI's. Providers should strive to offer patients with additional resources such as the opportunity for consultation with a specialist or a consultation service dedicated to informing patients about regenerative medicine.

Patients seeking stem cell therapies-a prospective qualitative analysis from a Regenerative Medicine Consult Service.

Despite patient demand for stem cell therapies (SCTs) for musculoskeletal conditions, there remains limited research on why patients seek SCTs or their sources of information. We employ three questions into a consult intake form: (1) Why are you interested in stem cell treatment for your condition? (2) How did you find out about stem cell treatment for your condition? (3) Have you contacted a stem cell clinic? Responses analyzed, using a qualitative content analysis approach to identify themes reveal many patients seek SCTs to treat pain or delay surgery which may align with some current clinical evidence while other patients express motivations as expected outcomes (e.g., SCTs are better than standard of care or can regenerate tissue) which are not supported by current medical evidence. These differences suggests that patient-centered counseling may help patients by addressing misconceptions and increasing health literacy about expected outcomes of SCTs for treating musculoskeletal conditions.

Opinion: Patient reported motivations for seeking stem cell therapy and considerations for counseling.

Stem cell therapies occupy a unique place in the American public's consciousness which has led to excessive enthusiasm over their potential to cure orthopedic conditions. Much has been written about direct-to-consumer marketing of cell therapies for a myriad of medical conditions. Far less has been studied on the attitudes that drive many patients to seek stem cell and orthobiologic therapies for musculoskeletal conditions. Previously published research on patient motivations for seeking stem cell therapy to treat orthopedic maladies such as osteoarthritis and chronic tendinopathies has shown that some patients were motivated by factors not supported by current medical evidence. These differing responses strongly suggest the need for patient-centered counseling to address misinformation about stem cell therapies for musculoskeletal conditions and increase health literacy about outcomes of orthobiologics.

American Medical Society for Sports Medicine Position Statement: Principles for the Responsible Use of Regenerative Medicine in Sports Medicine.

ABSTRACT: Many sports medicine physicians are currently considering introducing regenerative medicine into their practice. Regenerative medicine and the subclassification of orthobiologics are a complicated topic and have produced widely varying opinions. Although there is concern by government regulators, clinicians, scientists, patient advocacy organizations, and the media regarding the use of regenerative medicine products, there is also excitement about the potential benefits with growing evidence that certain regenerative medicine products are safe and potentially efficacious in treating musculoskeletal conditions. Sports medicine physicians would benefit from decision-making guidance about whether to introduce orthobiologics into their practice and how to do it responsibly. The purpose of this position statement is to provide sports medicine physicians with information regarding regenerative medicine terminology, a brief review of basic science and clinical studies within the subclassification of orthobiologics, regulatory considerations, and best practices for introducing regenerative medicine into clinical practice. This information will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine and orthobiologics in their practice.

Academic Physician Specialists' Approaches to Counseling Patients Interested in Unproven Stem Cell and Regenerative Therapies-A Qualitative Analysis.

OBJECTIVE: To explore the experiences, approaches, and challenges of physicians consulting patients about experimental stem cell and regenerative medicine interventions (SCRIs). PARTICIPANTS AND METHODS: From August 21, 2018, through July 30, 2019, semistructured interviews of 25 specialists in cardiology, ophthalmology, orthopedics, pulmonology, and neurology were conducted and qualitatively analyzed using modified grounded theory. RESULTS: All specialists used informational approaches to counsel patients, especially orthopedists. Informational approaches included explaining stem cell science, sharing risks, and providing principles. Several specialists also used relational counseling approaches including emphasizing that physicians want what is best for patients, acknowledging suffering, reassuring continued care, empathizing with patients and families, and underscoring that patients have the final decision. Many specialists reported being comfortable with the conversation, although some were less comfortable and several noted challenges in the consultation including wanting to support a patient's decision but worrying about harms from unproven SCRIs, navigating family pressure, and addressing stem cell hype and unrealistic expectations. Specialists also desired that additional resources be available for them and patients. CONCLUSION: Physicians relied more heavily on providing patients with information about SCRIs than using relational counseling approaches. Efforts should be directed at helping physicians address the informational and relational needs of patients, including providing tools and resources that inform physicians about the unproven SCRI industry, building skills in empathic communication, and the creation and dissemination of evidence-based resources to offer patients.

Biologic Association Annual Summit: 2020 Report.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

Complications Following Biologic Therapeutic Injections: A Multicenter Case Series.

PURPOSE: To describe the complications that occur following biologic therapeutic injections. METHODS: We queried physician members of the Biologic Association, a multidisciplinary organization dedicated to providing a unified voice for all matters related to musculoskeletal biologics and regenerative medicine. Patients included in this study must have (1) received a biologic injection, (2) sustained an adverse reaction, and (3) had a minimum of 1-year follow-up after the injection. Patient demographic information, medical comorbidities, diagnoses, and previous treatments were recorded. The type of injection, injection setting, injection manufacturers, and specific details about the complication and outcome were collected. RESULTS: In total, 14 patients were identified across 6 institutions in the United States (mean age 63 years, range: 36-83 years). The most common injections in this series were intra-articular knee injections (50%), followed intra-articular shoulder injections (21.4%). The most common underlying diagnosis was osteoarthritis (78.5%). Types of injections included umbilical cord blood, platelet-rich plasma, bone marrow aspirate concentrate, placental tissue, and unspecified "stem cell" injections. Complications included infection (50%), suspected sterile inflammatory response (42.9%), and a combination of both (7.1%). The most common pathogen identified from infection cases was Escherichia coli (n = 4). All patients who had isolated infections underwent treatment with at least one subsequent surgical intervention (mean: 3.6, range: 1-12) and intravenous antibiotic therapy. CONCLUSIONS: This study demonstrates that serious complications can occur following treatment with biologic injections, including infections requiring multiple surgical procedures and inflammatory reactions. LEVEL OF EVIDENCE: Level IV, case series.

Oil injection for cosmetic enhancement of the upper extremities: a case report and review of literature.

Here the authors report a case of complications occured after injection of a site enhancement oil in the upper extremity for cosmetic muscles' volume enhancement and a literature review on the topic. The medical and sports communities should be aware of the secondary effects of site enhancement oils use, which could bring to severe complications.

Glenohumeral Osteoarthritis: The Role for Orthobiologic Therapies: Platelet-Rich Plasma and Cell Therapies.

The glenohumeral (GH) joint ranks third on the list of the large joints that are most commonly affected by osteoarthritis, after the knee and the hip. General nonsurgical modalities, including changes in daily activities, physical therapy, pharmacotherapy, and corticosteroid injections, constitute the mainstay of treatment. Most of these options, however, have shown moderate and short-term effectiveness. Arthroplasty techniques have proven to be successful for elderly patients. Nevertheless, replacement options are not optimal for younger patients because their functional demands are higher and prostheses have a finite life span. This has led to the search for new nonoperative treatment options to target this subgroup of patients. It has been suggested that orthobiologic therapies, including platelet-rich plasma (PRP) and cell therapies, present great promise and opportunity for the treatment of GH osteoarthritis. Despite the promising results that have been shown by cell therapies and PRP for treating degenerative joint conditions, additional studies are needed to provide more definitive conclusions.

A Randomized, Controlled Pilot Trial Comparing Platelet-Rich Plasma to Topical Minoxidil Foam for Treatment of Androgenic Alopecia in Women.

BACKGROUND: Androgenic alopecia (AGA) is a common hair loss disorder. Studies have demonstrated successful treatment with platelet-rich plasma (PRP) in men, but studies in women are few. OBJECTIVE: To evaluate PRP in the treatment of AGA in women, compared with topical minoxidil. MATERIALS AND METHODS: Twenty women with AGA received topical minoxidil for 12 weeks and injectable PRP for 12 weeks in a randomized crossover design with an 8-week washout between treatments. Standardized TrichoScan analysis and quality-of-life questionnaires were assessed at baseline and 12-week follow-up for each treatment. RESULTS: After PRP, significant increases from baseline to Week 12 in TrichoScan analysis hair count (p = .002) and vellus hair density (p = .009) occurred. However, minoxidil resulted in significant increases in hair count (p < .001), vellus hair density (p = .03), terminal hair density (p = .004), and cumulative thickness (p = .004). Several quality of life responses improved from baseline to Week 12 after PRP treatment, whereas no improvements were noted after minoxidil. CONCLUSION: Platelet-rich plasma is an effective treatment for hair regrowth in female AGA, although not as effective as minoxidil. However, the improved quality of life responses after PRP, but not minoxidil, suggest a potential overall greater degree of satisfaction with PRP. LEVELS OF EVIDENCE: I. CLINICAL TRIAL REGISTRATION: NCT03488108.