Shapiro, Shane A.

Background: The presence of various growth factors in platelets makes platelet-rich plasma (PRP) 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 PRP compared with saline solution in women with aging skin of the hands. Methods: In this prospective, randomized clinical trial, 18 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 and at 12-week 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 2 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. Conclusions: 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 older than 45 years may be a factor accounting for nonresponse (ie, 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. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

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.

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.

AbstractSonography 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.

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.

Extracellular vesicles (EVs) are cell-released nanoparticles that transfer biomolecular content between cells. Among EV-associated biomolecules, microRNAs (miRNAs/miRs) represent one of the most important modulators of signaling pathways in recipient cells. Previous studies have shown that EVs from adipose-derived mesenchymal stromal cells (MSCs) and adipose tissue modulate inflammatory pathways in macrophages. In this study, the effects of miRNAs that are abundant in adipose tissue EVs and other biogenic nanoparticles (BiNPs) were assessed in terms of altering Toll-like receptor 4 (TLR4)-induced cytokines. TLR-4 signaling in macrophages is often triggered by pathogen or damage-induced inflammation and is associated with several diseases. This study demonstrates that miR-451a, which is abundant in adipose tissue BiNPs, suppresses pro-inflammatory cytokines and increases anti-inflammatory cytokines associated with the TLR4 pathway. Therefore, miR-451a may be partially responsible for immunomodulatory effects of adipose tissue-derived BiNPs.

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.

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.

Abstract 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.