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.

Academic physician specialists' views toward the unproven stem cell intervention industry: areas of common ground and divergence.

BACKGROUND AND AIMS: Premature commercialization of unproven stem cell interventions (SCIs) has received significant attention within the regenerative medicine community. Patients considering SCIs may encounter misinformation and seek out guidance from their physicians who are trusted brokers of health information. However, little is known about the perspectives of academic physician specialists toward the SCI industry. The purpose of this study was to capture the attitudes of physician specialists with experience addressing patient questions about unproven SCIs. METHODS: The authors undertook 25 semi-structured interviews with academic physicians in cardiology, ophthalmology, orthopedics, pulmonology and neurology primarily from one academic center. RESULTS: The authors identified two major themes: concerns and mediators of appropriateness of offering SCIs as therapies to patients. Specialists were generally aware of the industry and reported scientific and commercial concerns, including the scientific uncertainty of SCIs, medical harms to patients, misleading marketing and its impact on patient informed consent and economic harms due to large out-of-pocket costs for patients. All specialists outside of orthopedics voiced that it was inappropriate to be offering SCIs to patients today. These views were informed by previously expressed concerns surrounding safety and properly informing patients, levels of evidence needed prior to offering SCIs therapeutically and desired qualifications for clinicians. Among the specialties, orthopedists reported that under certain conditions, SCIs may be appropriate for patients with limited clinical options but only when safety is adequate, expectations are managed and patients are well informed about the risks and chances of benefit. Most participants expressed a desire for phase 3 studies and Food and Drug Administration approval prior to marketing SCIs, but some also shared the challenges associated with upholding these thresholds of evidence, especially when caring for out-of-option patients. CONCLUSIONS: The authors' results suggest that medical specialists are aware of the industry and express several concerns surrounding SCIs but differ in their views on the appropriateness and clinical evidence necessary for offering SCIs currently to patients. Additional educational tools may help physicians with patient engagement and expectation management surrounding SCIs.

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.

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.

Adipose-Derived Biogenic Nanoparticles for Suppression of Inflammation.

Extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti-inflammatory properties of adipose tissue-derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC-EVs, lipoaspirate nanoparticles (Lipo-NPs) take less time to process (hours compared to months) and cost less to produce (clinical-grade cell culture facilities are not required). The physicochemical characteristics and anti-inflammatory properties of Lipo-NPs are evaluated and compared to those of patient-matched ADSC-EVs. Moreover, guanabenz loading in Lipo-NPs is evaluated for enhanced anti-inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo-NPs compared to ADSC-EVs. Additionally, the uptake of Lipo-NPs in hepatocytes and macrophages is higher. Lipo-NPs and ADSC-EVs have comparable protective and anti-inflammatory effects. Specifically, Lipo-NPs reduce toll-like receptor 4-induced secretion of inflammatory cytokines in macrophages. Guanabenz-loaded Lipo-NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.

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.

Organotropic drug delivery: Synthetic nanoparticles and extracellular vesicles.

Most clinically approved drugs (primarily small molecules or antibodies) are rapidly cleared from circulation and distribute throughout the body. As a consequence, only a small portion of the dose accumulates at the target site, leading to low efficacy and adverse side effects. Therefore, new delivery strategies are necessary to increase organ and tissue-specific delivery of therapeutic agents. Nanoparticles provide a promising approach for prolonging the circulation time and improving the biodistribution of drugs. However, nanoparticles display several limitations, such as clearance by the immune systems and impaired diffusion in the tissue microenvironment. To overcome common nanoparticle limitations various functionalization and targeting strategies have been proposed. This review will discuss synthetic nanoparticle and extracellular vesicle delivery strategies that exploit organ-specific features to enhance drug accumulation at the target site.

An Academic Dermatology Center's Structured Platelet-rich Plasma Approach to Patients with Androgenetic Alopecia.

Androgenetic alopecia (AGA) is a prevalent cause of hair loss with complex pathophysiologic mechanisms that pose challenges for effective treatment. Despite various therapeutic approaches yielding only partial results, regenerative treatments, such as platelet-rich plasma (PRP), have gained popularity. However, the lack of standardized PRP practices, encompassing product preparation and application, has been a significant concern. This article aims to contribute to fill this gap by presenting a comprehensive overview of PRP practices at a large academic center. Through detailing our protocols, this work not only contributes to the understanding of AGA treatment but also emphasizes the crucial aspect of treatment standardization in the context of PRP therapy. By providing a practical representation of our institutional PRP practices, we aim to contribute to the ongoing discourse on refining and implementing standardized protocols, fostering reproducibility, and improving clinical outcomes in the management of AGA.

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.

Designing persuasive health education for patients seeking unproven stem cell interventions.

Misinformation among clinics advertising unproven stem cell interventions (SCIs) is pervasive and has resulted in patient and societal harms. Most bioethics commentaries have centered on advancing regulatory approaches to curtail the supply side of the market, but insufficient attention has been paid to considering strategies influencing patient demand. In this article, we offer an ethical justification for the design and deployment of persuasive patient education on unproven SCIs and distinguish it from didactic and manipulative education frames. Persuasive education should aim to correct and inoculate against misinformation about unproven SCIs and instill a sense of caution among patients considering experimental interventions outside of a clinical trial. We outline various communication strategies to effectively correct or inoculate against SCI misinformation. The stem cell community needs to invest in understanding patients' informational sources, attitudes, and beliefs about SCIs to develop and implement evidence-based persuasive education to promote informed decision-making about these therapies.

A Pilot, Randomized, Single-Blind, Controlled Study Evaluating the Use of Platelet Rich Plasma (PRP) for Hand Skin Rejuvenation.

BACKGROUND: The presence of various growth factors in platelets makes platelet rich plasma a powerful tool in the stimulation of collagen regeneration in aging skin. The main objective of this study was to determine efficacy and safety of platelet rich plasma compared to saline solution in women with aging skin of the hands. METHODS: In this prospective, randomized clinical trial, eighteen women with hand aging received PRP injections every 4 weeks into the unilateral dorsal hand for 12 weeks total; with saline injections into the contralateral hand in a randomized, controlled, single-blind fashion. Physician assessment, photographs and quality-of-life questionnaires were used for assessment at baseline; 12- and 24-week follow-up. RESULTS: The majority of patients reported pain and discomfort along with a burning/stinging sensation in both PRP and saline treated hands with no significant differences noted in any patient outcome measures between the two treatments (all P≥0.25). No differences were reliably detected between the treatment hands by a blinded investigator comparing before and after clinical photographs of the hands. CONCLUSION: Three injections of PRP spaced 4 weeks apart did not appear to be effective for treatment of aging skin of the hands in women, with no noted difference as compared with baseline, or saline injection. Although age > 45 years may be a factor accounting for non-response (i.e., subtle skin changes are difficult to appreciate, and possible limited platelet regenerative capacity in advanced age) it appears that PRP is not a reliable cosmetic option for management of hand aging.

From Dugout to the Mound: A Tale of Platelet-Rich Performance.

Ulnar collateral ligament (UCL) tears of the elbow are prevalent injuries among throwing athletes and are associated with excessive or repeated valgus forces at the elbow. We present the case of an 18-year-old male baseball pitcher with an 18-month history of progressive right elbow pain, notably worsened during his fastball pitching. Clinical assessment revealed tenderness with dynamic stressing of the right UCL. Imaging analyses, including magnetic resonance imaging (MRI) and dynamic ultrasound, confirmed a high-grade partial tear of the UCL at its origin. Non-operative management was pursued, which included an ultrasound-guided platelet-rich plasma (PRP) injection and intensive physical therapy. Follow-up evaluations at six and 12 weeks demonstrated a noteworthy improvement in subjective pain descriptions and structural healing of the UCL. After the patient completed a therapy and rehabilitation program, throwing activities at full strength were able to be resumed. This case underscores the potential efficacy of conservative approaches in handling UCL tears with the inclusion of PRP as a viable treatment option.

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.

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.

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.

Sucrose-based cryoprotective storage of extracellular vesicles.

Advancements in extracellular vesicle (EV) studies necessitate the development of optimized storage conditions to ensure preservation of physical and biochemical characteristics. In this study, the most common buffer for EV storage (phosphate-buffered saline/PBS) was compared to a cryoprotective 5% sucrose solution. The size distribution and concentration of EVs from two different sources changed to a greater extent after -80 °C storage in PBS compared to the sucrose solution. Additionally, molecular surface protrusions and transmembrane proteins were more prevalent in EVs stored in the sucrose solution compared to those stored in PBS. This study demonstrates, for the first time, that distinct ring-like molecular complexes and cristae-like folded membranous structures are visible upon EV degradation. Taken together, the size, concentration, molecular surface extensions, and transmembrane proteins of EVs varied substantially based on the buffer used for -80 °C storage, suggesting that biocompatible cryoprotectants, such as sucrose, should be considered for EV studies.