Aims

Knee osteoarthritis (OA) is characterized by a chronic inflammatory process involving multiple cytokine pathways, leading to articular cartilage degeneration. Intra-articular therapies using pharmaceutical or autologous anti-inflammatory factors offer potential non-surgical treatment options. Autologous protein solution (APS) is one such product that uses the patient’s blood to produce a concentrate of cells and anti-inflammatory cytokines. This study evaluated the effect of a specific APS intra-articular injection (nSTRIDE) on patient-reported outcome measures compared to saline in moderate knee OA.

Background. The PATH-2 trial found no evidence of a benefit of Platelet Rich Plasma (PRP) injection versus a placebo after Achilles tendon rupture (ATR) at six-months. ATR often leave longer-term functional deficiencies beyond six-months. This study aim is to determine if PRP affect tendon functional outcomes at two-years after rupture. Study design. Randomised multi-centre two-arm parallel-group, participant- and assessor-blinded, superiority trial. Methods. Adults with acute ATR managed non-surgically were recruited in 19 UK hospitals from 2015 to 2019. Exclusions were insertion or musculotendinous injuries, leg injury or deformity, diabetes, haematological disorder, corticosteroids and anticoagulation therapy. Participants were randomised via an online system 1:1 to PRP or placebo. Primary outcome was Achilles Tendon Rupture Score (ATRS) at two-years. Secondary outcomes were pain, Patient-Specific Functional Scale (PSFS), SF-12 and re-rupture. Assessors were blinded. Intention-to-treat and Compliance Average Causal effects (CACE) analyses were carried out. Consistency of effects across subgroups age, BMI, smoking and gender were assessed using Forest plots. Pearson's correlation was used to explore ATRS correlation with blood and growth factors. Results. 216/230 (94%) participants completed the 6-months follow-up were contacted. 182/216 (84%) completed the two-year follow-up. Participants were aged mean 46 (SD 13.0), 57 female/159 male. 96% received the allocated intervention. Two-years ATRS scores were 82.2 (SD 18.3) in the PRP group (n=85) and 83.8 (SD 16.0) in the placebo group (n=92). There was no evidence of a difference in the two-years ATRS (adjusted-mean difference −0.752 95%CI −5.523 to 4.020, p=0.757), or in any secondary outcome, and no re-rupture between at two-years. Neither PRP cellular or growth factors correlated with the two-year ATRS. Conclusion. PRP did not improve patient-reported function or quality of life two-years after acute Achilles tendon rupture, compared with placebo, indicating that PRP offers no patient benefit in the longer term

Background. Disability and slow return to sport and work after tendon rupture are major challenges. Platelet Rich Plasma (PRP) is an autologous supraphysiological concentration of platelets from whole blood that has demonstrated positive cellular and physiological effects on healing in laboratory conditions but evidence from adequately powered robust clinical trials is lacking. We aimed to determine the clinical efficacy of PRP for treatment of acute Achilles tendon rupture. Methods. In a placebo-controlled, participant- and assessor-blinded, trial at 19 NHS hospitals we randomly assigned 230 adults starting acute Achilles rupture non-surgical management to PRP injection or dry-needle insertion (placebo) to the rupture gap under local anaesthetic. Patients with confounding or contraindicated concurrent medical conditions were excluded. The primary outcome was muscle-tendon function, assessed by the limb symmetry index (LSI, uninjured limb/injured limb × 100, higher scores better) of the work (Joules) performed during the heel-rise endurance test at 24 weeks. Secondary outcomes were: Achilles Tendon Rupture Score (ATRS, 0–100, higher scores better), quality of life (SF-12), pain, and goal attainment. Trial registration: ISRCTN54992179. Results. Participants were aged mean 46 years and 57 (25%) were female. 103/114 (90%) of the PRP group and all (n=116) in the placebo group received allocated treatment. At 24 weeks, mean LSI was 34.4 for the PRP group and 38.8 for placebo (adjusted mean difference −4.4 95% CI −11.2 to 2.5, n=201) and ATRS was mean 65.2 PRP vs 65.8 (adjusted mean difference −0.6, 95% CI −4.9 to 3.7, n=224). There were no differences between groups in the other secondary outcomes. Conclusion. We found no evidence of PRP efficacy for improving muscle-tendon function or patient-reported recovery after acute Achilles tendon rupture. Our findings challenge the increasing global use of PRP for acute tendon injury and indicate that robust evaluations are required in other applications

Platelet Rich Plasma (PRP), either rich (L-PRP) or poor (P-PRP) of leukocytes, is frequently used as an anti-inflammatory and regenerative tool in osteoarthritis (OA). PRP contains proteins but not genes as it is derived from megakaryocytes. Proteomics but not metabolomics of PRP was recently studied. Metabolomics is a field of ‘omics’ research involved in comprehensive portrayal of the small molecules, metabolites, in the metabolome. These small molecules can be endogenous metabolites or exogenous compounds found in an organism (1). Our aim was to determine the difference between L-PRP and P-PRP. A cross-sectional clinical study was designed in six recreational male athletes between the ages of 18 and 35 years. 3 mL P-PRP and 3 mL -LPRP was prepared from 60 mL of venous blood after treating with 9 mL of sodium citrate and centrifugation at 2.700 rpm for 10 min. Half of the prepared PRP's were frozen at −20°C for a week. Fresh and frozen samples were analyzed at the Q-TOF LC/MS device after thawing to room temperature. Untargeted metabolomic results revealed that the metabolomic profile of the L-PRP and P-PRP were significantly different from each other. A total of 33.438 peaks were found. Statistically significant (p<0.05) peaks were uploaded to the MetaboAnalyst 5.0 platform. Exogenous out of 2.308 metabolites were eliminated and metabolites found significant for our study were subjected to pathway analysis. Steroid biosynthesis, sphingolipid metabolism and metabolism of lipid pathways were affected. In the L-PRP samples, Nicotinamide riboside (FC: 2.2), MHPG (FC: 3.0), estrone sulfate (FC: 7.5), thiamine diphosphate (FC: 2.0), leukotriene E4 (FC: 7.5), PC(18:1 (9Z)e/2:0) (FC: 9.8) and Ap4A (FC: 2.1) were higher compared to P-PRP. C24 sulfatide (FC: −11.8), 3-hexaprenyl-4,5-dihydroxybenzoic acid (FC: −2.8) metabolites were furthermore lower in P-PRP. Clinical outcomes of PRP application should consider these metabolic pathways in future studies (2)

Degenerative disc disease, associated to low back pain, afflicts more than 50% of humans, and represents a major healthcare problem, especially for the pathology initiation. Current treatments range from conservative strategies to more invasive surgical techniques, such as disc removal and vertebral fusion. In the Intervertebral Disease (IVD) the nucleus pulposus (NP) degeneration is a key factor for the pathology initiation. Several tissue engineering approaches aiming to restore the appropriate NP cell (NPCs) and matrix content, were attempted by using adult stromal cells either from bone marrow or adipose tissue, chondrocytes, notochordal cells and more recently also pluripotent stem cells. However, none was fully satisfactory since the NP acid and a-vascularized environment appeared averse to the implanted heterologous cells. Several studies demonstrated the efficacy of platelet derivatives such as platelet rich plasma (PRP) in promoting the regeneration of connective tissues. We investigated the efficacy of PRP on NPCs proliferation and differentiation with the goal to propose the direct stimulation of resident cells (stimulation of endogenous cells – less invasive surgical procedure) or the implantation of NPCs expanded in vitro in the presence of PRP as therapeutic agents in IVD degeneration. NPCs were isolated from small fragments of NP explants, cultivated in medium supplemented with PRP or FCS (standard condition control) and characterized by FACS analysis for the expression of the typical mesenchymal stem cells markers CD34, CD44, CD45, CD73, CD90 and CD105. NPCs cultured in PL showed a phenotypic profile like the cells cultured in FCS. However, compared to NPCs expanded in the presence of FCS, NPCs expanded in PRP showed a much better proliferation and differentiation capacity. NPCs differentiation was evaluated by the cell ability to produce an organized metachromatic cartilaginous matrix, confirmed by the positive immunohistochemical staining for chondrogenic markers

Disease modifying approaches are commonly applied in OA patients. An aging society with better life expectancies is increasing in Europe and the globe. Orthobiologics cover intraarticular hyaluronan injections and also cellular therapies. Cellular therapies range from platelet rich plasma (PRP) applications to exosomes. Short term follow-up of limited number of patients revealed favorable results in clinical cellular therapies. Most of these studies evaluated decrease of pain and increase in function. Recent basic science studies focused on the action mechanism of orthobiologic therapies however patient perspective is less studied. Our research team has recently performed a qualitative study on the patient perspective of hyaluronan injection of the knee joint. Findings of that study will be shared and future patient knowledge based options on orthobiologics will be discussed

Aims

Platelet-rich plasma (PRP) intra-articular injections may provide a simple and minimally invasive treatment for early-stage knee osteoarthritis (OA). This has led to an increase in its adoption as a treatment for knee OA, although there is uncertainty about its efficacy and benefit. We hypothesized that patients with early-stage symptomatic knee OA who receive multiple PRP injections will have better clinical outcomes than those receiving single PRP or placebo injections.

Aims. The aim of this study was to prepare a scoping review to investigate the use of biologic therapies in the treatment of musculoskeletal injuries in professional and Olympic athletes. Methods. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews and Arksey and O’Malley frameworks were followed. A three-step search strategy identified relevant published primary and secondary studies, as well as grey literature. The identified studies were screened with criteria for inclusion comprising clinical studies evaluating the use of biologic therapies in professional and Olympic athletes, systematic reviews, consensus statements, and conference proceedings. Data were extracted using a standardized tool to form a descriptive analysis and a thematic summary. Results. A total of 202 studies were initially identified, and 35 met criteria for the scoping review; 33 (94.3%) were published within the last eight years, and 18 (51.4%) originated from the USA. Platelet rich plasma was the most studied biologic therapy, being evaluated in 33 (94.3%) studies. Ulnar collateral ligament and hamstring injuries were the conditions most studied (nine (25.7%) studies and seven (20.0%) studies, respectively). Athletes most frequently participated in baseball, soccer, and American football. Only two (5.7%) studies were level 1 evidence, with interpretation and comparison between studies limited by the variations in the injury profile, biologic preparations, and rehabilitation protocols. Conclusion. There is diverse use of biologic therapies in the management of musculoskeletal injuries in professional and Olympic athletes. There is currently insufficient high-level evidence to support the widespread use of biologic therapies in athletes. Further research priorities include the development of condition/pathology-specific preparations of biologic therapies, and of outcome measures and imaging modalities sufficiently sensitive to detect differences in outcomes, should they exist. Cite this article: Bone Joint J 2021;103-B(7):1189–1196

Abstract. Background. Lateral and medial epicondylitis, more commonly known as Tennis and Golfer's elbow, can cause chronic pain and significant functional impairment in working-age patients. For patients with refractory epicondylitis, platelet rich plasma (PRP) of which ACP is a type, is commonly used as an alternative to surgical intervention, but its efficacy is unproven. Objective. To assess the mid-term outcomes of ultrasound guided ACP injections for patients with refractory epicondylitis who have failed conventional conservative treatment. Methods. 77 patients who were treated with PRP for refractory epicondylitis were included in the study. The mean age of patients was 50.3 years (range 36–70), with 30% men and 70% women. The Oxford Elbow Score (OES) and progression to surgery were used to assess the mid-term outcomes. Results. The mean follow up duration was 2.1 years (range 1.0 – 4.2). Post-procedure OES was recorded for thirty-three patients, of these, thirty-one patients (94.0%) demonstrated an improvement in their OES at mid-term follow-up compared to their pre-op score. The mean change in OES was +16 (range −7 to +34), 81.8% exhibited a minimally important change (MIC) in OES of greater than 8.2 points. Of all seventy-seven patients, seventeen (22.1%) underwent open release and twenty-seven (35.1%) patients were lost to follow up. Conclusion. Ultrasound guided ACP injections can be an effective treatment for refractory epicondylitis and is likely to prevent the need for surgery. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aims

Despite the increase in the surgical repair of proximal hamstring tears, there exists a lack of consensus in the optimal timing for surgery. There is also disagreement on how partial tears managed surgically compare with complete tears repaired surgically. This study aims to compare the mid-term functional outcomes in, and operating time required for, complete and partial proximal hamstring avulsions, that are repaired both acutely and chronically.

Injured skeletal muscle repairs spontaneously via regeneration, however, this process is often incomplete because of fibrotic tissue formation. In our study we wanted to show improved efficiency of regeneration process induced by antifibrotic agent decorin in a combination with Platelet Rich Plasma (PRP)-derived growth factors. A novel human myoblast cell (hMC) culture, defined as CD56 (NCAM)+ developed in our laboratory, was used for evaluation of potential bioactivity of PRP and decorin. To determine the their effect on the viability of hMC we performed a MTT assay. To perform the cell proliferation assay, hMCs were separately seeded on plates at a concentration of 30 viable cells per well. Cell growth medium prepared with different concentrations of PRP exudates (5%, 10%, and 20%) and decorin (10 ng/mL, 25 ng/mL, and 50 ng/mL) were added and incubated for 7 days. After incubation we stained the cells with crystal-violet and measured the absorbance. To study the expression of Transforming Growth Factor Beta (TGF-β) and myostatin (MSTN), two main fibrotic factors in the process of muscle regeneration we performed several ELISA assays in groups treated with all therapeutic agents (PRP, decorin and their combination). Further, we have studied the ability of these agents to influence the differential cascade of dormant myoblasts towards fully differentiated myotubes by monitoring step wise activation of single nuclear factors like MyoD and Myogenin via multicolor flow cytometry. We stained the cells simultaneously with antibodies against CD56, MyoD and myogenin. We acquired cell images of 5,000 events per sample at 40 x magnification using 488 nm and 658 nm lasers and fluorescence was collected using three spectral detection channels. We analysed the cells populations according to expression of single or multiple markers and their ratios. Finally, we examined the treated cell populations using a multicolour laser microscope after staining for desmin (a key marker of myogenic differentiation of hMC), α-tubulin, and nuclei. Optical images were acquired at the center of chamber slides where the cell density is at its highest using a Leica TCS SP5 II confocal microscope and analysed using Photoshop CS6, where a “Color Range” tool was used in combination with a histogram palette to count the pixels that correspond to desmin-positive areas in an image. The mitochondrial activity of cells, as determined by the MTT assay, was significantly increased (p < 0 .001) after exposure to tested concentrations of PRP exudate. Similarly, viability was elevated in all tested concentrations of decorin. PRP exudate enhanced the viability of cells to more than 400% when compared to the control (p < 0 .001). The viability of cells treated with PRP exudates was also significantly higher when compared to decorin (p < 0 .001). Decorin did not show a significant effect on cell proliferation compared to the control, however, cultivation with PRP exudate leads to a 5-fold increase in cell proliferation (p < 0 .001). Decorin was shown to down-regulate the expression of TGF-β when compared to the control by more than 15% (p < 0 .001) but significantly less than PRP exudate p < 0 .005). PRP significantly down-regulated TGF-β expression by more than 30% (p < 0 .001). Similarly, the MSTN expression levels were significantly down-regulated by decorin and PRP. MSTN levels of cells treated with decorin were decreased by 28.4% (p < 0 .001) and 23.1% by PRP (p < 0 .001) when compared to the control group. Using flow cytometry we detected a 39.1% increase in count of myogenin positive cells in the PRP-treated group compared to the control. Moreover, there was a 3.09% increase in cells positive only for myogenin, whereas no such cells were found in the control cell population. The population of cells positive only for myogenin is considered as fully differentiated and capable of fusion into myotubes as well as future mucle fibers and is thus of great importance for muscle regeneration. At the same time 20.6% fewer cells remained quiescent (positive only for CD56). Cells positive for both MyoD and myogenin represent the population that shifted significantly towards mature myocites during myogenesis but are not yet fully committed. Finally, a statistically significant up-regulation of desmin expression (p < 0 .01 for the PRP treated group, p < 0 .005 for the decorin and PRP + decorin treated groups) was present in all therapeutic groups when compared to the control. While no significant difference was found between the PRP and decorin-treated groups, their combination led to a more than 3-fold increase (p < 0 .005) of desmin expression when compared to single bioactives. PRP can be a highly potential therapeutic agent for skeletal muscle regeneration and repair, especially if in combination with a TGF-β antagonis decorin. Achieving better healing could likely result in faster return to play and lower reinjury rate

Aims. For cementless implants, stability is initially attained by an interference fit into the bone and osteo-integration may be encouraged by coating the implant with bioactive substances. Blood based autologous glue provides an easy, cost-effective way of obtaining high concentrations of growth factors for tissue healing and regeneration with the intention of spraying it onto the implant surface during surgery. The aim of this study was to incorporate nucleated cells from autologous bone marrow (BM) aspirate into gels made from the patient’s own blood, and to investigate the effects of incorporating three different concentrations of platelet rich plasma (PRP) on the proliferation and viability of the cells in the gel. Methods. The autologous blood glue (ABG) that constituted 1.25, 2.5, and 5 times concentration PRP were made with and without equal volumes of BM nucleated cells. Proliferation, morphology, and viability of the cells in the glue was measured at days 7 and 14 and compared to cells seeded in fibrin glue. Results. Overall, 2.5 times concentration of PRP in ABG was capable of supporting the maximum growth of cells isolated from the BM aspirate and maintain their characteristics. Irrespective of PRP concentration, cells in ABG had statistically significantly higher viability compared to cells in fibrin glue. Conclusion. In vitro this novel autologous gel is more capable of supporting the growth of cells in its structure for up to 14 days, compared to commercially available fibrin-based sealants, and this difference was statistically significant. Cite this article: Bone Joint Res 2020;9(7):402–411

There is good scientific rationale to support the use of growth factors to promote musculoskeletal tissue regeneration. However, the clinical effectiveness of platelet-rich plasma (PRP) and other blood-derived products has yet to be proven. Characterization and reporting of PRP preparation protocols utilized in clinical trials for the treatment of musculoskeletal disease is highly inconsistent, and the majority of studies do not provide sufficient information to allow the protocols to be reproduced. Furthermore, the reporting of blood-derived products in orthopaedics is limited by the multiple PRP classification systems available, which makes comparison of results between studies challenging. Several attempts have been made to characterize and classify PRP; however, no consensus has been reached, and there is lack of a comprehensive and validated classification. In this annotation, we outline existing systems used to classify preparations of PRP, highlighting their advantages and limitations. There remains a need for standardized universal nomenclature to describe biological therapies, as well as a comprehensive and reproducible classification system for autologous blood-derived products.

Cite this article: Bone Joint J 2019;101-B:891–896.

Biologic supplementation and augmentation techniques have become popular in recent years. There has been considerable media attention regarding professional athletes and celebrities who have traveled around the world to receive treatments using proprietary cocktails of platelet rich plasma, bone marrow aspirate concentrates, extracellular matrix, adipose-derived stem cells, human as well as xenograft derived collagen implants and protein supplements among other components. Unfortunately, the medical evidence regarding these treatments has often been inconsistent, inadequate with respect to levels of evidence with a dearth of mid- and long-term data to guide our treatments. This presentation will review the data available regarding the treatment of rotator cuff tendinosis, partial thickness rotator cuff tears, full thickness rotator cuff tears and osteoarthritis of the glenohumeral joint. Unfortunately, there are more questions than answers regarding the use of biologics

Arthrosis of the hip joint can be a significant source of pain and dysfunction. While hip replacement surgery has emerged as the gold standard for the treatment of end stage coxarthrosis, there are several non-arthroplasty management options that can help patients with mild and moderate hip arthritis. Therefore, the purpose of this paper is to review early prophylactic interventions that may help defer or avoid hip arthroplasty. Nonoperative management for the symptomatic hip involves minimizing joint inflammation and maximizing joint mobility through intra-articular joint injections and exercise therapy. While weight loss, activity modifications, and low impact exercises is generally recommended for patients with arthritis, the effects of these modalities on joint strength and mobility are highly variable. Intra-articular steroid injections tended to offer reliable short-term pain relief (3–4 weeks) but provided unreliable long-term efficacy. Additionally, injections of hyaluronic acid do not appear to provide improved pain relief compared to other modalities. Finally, platelet rich plasma injections do not perform better than HA injections for patients with moderate hip joint arthrosis. Primary hip joint arthrosis is rare, and therefore treatment such as peri-acetabular osteotomies, surgical dislocations, and hip arthroscopy and related procedures are aimed to minimise symptoms but potentially aim to alter the natural history of hip diseases. The state of the articular cartilage at the time of surgery is critical to the success or failure of any joint preservation procedures. Lech et al. reported in a series of dysplastic patients undergoing periacetabular osteotomies that one third of hips survived 30 years without progression of arthritis or conversion to THA. Similarly, surgical dislocation of the hip, while effective for treatment of femoroacetabular impingement, carries a high re-operation rate at 7 years follow up. Finally, as the prevalence of hip arthroscopic procedures continues to rise, it is important to recognise that failure to address the underlying structural pathologies can lead to failure and rapid joint destruction. In summary, several treatment modalities are available for the management of hip pain and dysfunction in patients with a preserved joint space. While joint preservation procedures can help improve pain and function, they rarely alter the natural history of hip disease. The status of the articular cartilage at the time of surgery is the most important predictor of treatment success or failure

Aims

Local antibiotics are used in the surgical management of foot infection in diabetic patients. This systematic review analyzes the available evidence of the use of local antibiotic delivery systems as an adjunct to surgery.

The goal of surgery for osteochondral lesions is to regenerate the damaged cartilage with ideally hyaline cartilage. The current gold standard treatment is bone marrow stimulation (BMS) by microfracture. In reality however BMS typically results in the generation of fibrocartilage. Orthobiologics including bone marrow aspirate, platelet rich plasma and hyaluronic acid products have been shown to promote cartilage healing and potentially increase the formation of hyaline cartilage in treated lesions. However the role of these products, the timing of their administration and frequency of application are still not clearly defined and their routine use is still not recommended. These issues and future directions for research and future clinical application will be discussed