Orthobiologics in knee osteoarthritis, dream or reality?

Cartilage restoration or repair, also known as orthobiologic therapy, is indicated after the failure of conservative or supportive treatment. However, there is paucity in evidence supporting the efficacy of orthobiologic therapy. The blood-derived products, such as platelet-rich plasma (PRP), is one of the commonly used orthobiologic therapy for knee osteoarthritis. Several studies have shown that PRP is superior to other treatments, but the anatomic changes are scarce. Treatment with mesenchymal stem cells (MSCs) offers the greatest potential for curing degenerative disease due to their self-renewal ability, ability to migrate towards injured tissues (homing/trafficking), and ability to promote repair and regeneration of osteochondral defects. However, ethical concerns and high costs remain major challenges associated with MSC therapy. Gene therapy, another promising orthobiologic therapy, is currently in phase II clinical trial and has shown promising results. The key factors for successful orthobiologic therapy include patient selection, appropriate dosing, treatment of underlying mechanical problems, age, severity, and cost-effectiveness.

Human Amniotic Allograft in Hand Surgery.

Amnion epithelial and mesenchymal cells have been shown in vitro to contain a variety of regulatory mediators that result in the promotion of cellular proliferation, differentiation, and epithelialization and the inhibition of fibrosis, immune rejection, inflammation, and bacterial invasion. Amniotic membrane-based products are approved for use as human cells, tissues, and cellular- and tissue-based products through Sections 361 or 351 of the Food and Drug Administration. Previously reported clinical applications of human amniotic membranes include nerve repair, tendon injury, joint and cartilage damage, and wound management. Although there is some evidence regarding the use of amniotic allografts in animals, there is a paucity of literature regarding their use in treating pathology of the hand and wrist. Further investigation is necessary to determine their effectiveness and therapeutic value in the upper extremity.

Orthobiologics in Hand Surgery.

Orthobiologic agents are used as innovative adjuvant therapy to treat common upper-extremity pathology, including carpal tunnel syndrome, de Quervain tenosynovitis, and distal radius fractures. In this article, we perform a narrative review and evaluate current literature on orthobiologics in the upper extremity. Orthobiologics evaluated include bone morphogenetic proteins, platelet-rich plasma, bone marrow aspirate concentrate, mesenchymal stem cells, and amniotic membrane. Studies selected include randomized control trials, case studies, and animal studies. Although there is some clinical evidence regarding the use of orthobiologic agents in the treatment of shoulder, elbow, and sports injuries, there is a paucity of literature regarding their use to treat pathology of the hand and wrist. Further investigation is necessary to determine their effectiveness and therapeutic value in treatment of upper extremity injuries.

Ideal xenograft or a perfect bone substitute?-A retrospective review and analysis of the historical concept of ivory implants in orthopaedics.

PURPOSE: Surgical treatment of fractures has evolved with the development of anaesthesia in 1846. Experiments with different implants both organic and non-organic had led to introduction of sometimes extremely peculiar materials coming from different species like ox bone or elephant's ivory. The aim of this article is to present not widely known concept of ivory use in bone surgery that set its foot in the history of orthopaedics and laid foundations for orthobiologic reconstructions. METHODS: Retrospective analysis of articles and books published between 1846 and 2017 that describe various examples of ivory application in the treatment of fresh fractures, non-unions and reconstruction of joints. RESULTS: Our research shows that ivory to the surgical world was introduced by Friedrich Dieffenbach, founder of the modern plastic surgery. It was also used with different rate of success by many of the famous surgeons of the nineteenth and twentieth century to include Trendelenburg, Billroth, Volkmann, Paget and Hey Groves. Ivory was immensely popular in bone surgery and became material of choice demonstrating amazing biological properties and very low rate of infections. CONCLUSION: Ivory has served well in successful treatment of various orthopaedic conditions for over 100 years. In this article, we are using history as a stepping stone to examine material that is not rejected by the body and promotes bony healing without increased infection or other complications. It is worth considering further analysis of historically acquired specimens for further development of materials for further orthopaedic fracture and reconstructive techniques.

Outcomes of Hindfoot Arthrodesis Supplemented With Bioactive Glass and Bone Marrow Aspirate: A Retrospective Radiographic Study.

Foot and ankle surgeons continue to explore bone graft alternatives that will be comparable to the reference standard of autologous bone. The purpose of the present study was to consider the outcomes of hindfoot arthrodesis supplemented with bioactive glass in patients at risk of delayed union and nonunion. We performed a retrospective radiographic review of 29 consecutive patients (48 joints) who had undergone arthrodesis of ≥1 joint of the hindfoot (ankle, subtalar, talonavicular, calcaneocuboid). All patients included in the present study had a minimum of 1 documented risk factor for osseous nonunion (history of previous nonunion, trauma, smoking, diabetes, Charcot arthropathy, obesity, age >65 years at surgery). The patients were followed up for a minimum of 24 weeks or until radiographic healing had been achieved. We found 12 (25.0%) nonunions across all 48 joints supplemented with bioactive glass. We found 4 (16.7%) nonunions in the subtalar joint, 1 (11.1%) in the calcaneocuboid joint, and 1 (11.1%) in the talonavicular joint. We found that hindfoot arthrodesis procedures supplemented with bioactive glass resulted in an incidence of union comparable to that with autograft and other bone graft substitutes.

Assessment of Multipotent Mesenchymal Stromal Cells in Bone Marrow Aspirate From Human Calcaneus.

Bone marrow aspirates (BMAs), owing to their innate osteogenic potential, are well-documented supplements to osteoconductive and/or osteoinductive materials. The calcaneal body provides foot and ankle surgeons a convenient harvest site with low morbidity and minimal cost. In the present study, we sought to identify and characterize multipotent mesenchymal stromal cells (MSCs) in BMAs harvested from the human calcaneal body. Ten healthy patients aged 18 to 65 years were enrolled in the present study. BMAs were harvested from the patients without any reported postoperative complications related to the harvest. Cells isolated from all the aspirates were adherent to culture plates and expressed positive MSC surface markers (CD105, CD90, and CD73) and a low level of negative MSC markers (CD34 and CD45). The cells maintained the ability to proliferate and differentiate into cells of mesenchymal lineages. The BMAs from the human calcaneal body offer a healthy source of multipotent MSCs.

Treatment of Equine Tarsus Long Medial Collateral Ligament Desmitis with Allogenic Synovial Membrane Mesenchymal Stem/Stromal Cells Enhanced by Umbilical Cord Mesenchymal Stem/Stromal Cell-Derived Conditioned Medium: Proof of Concept.

Horses are high-performance athletes prone to sportive injuries such as tendonitis and desmitis. The formation of fibrous tissue in tendon repair remains a challenge to overcome. This impels regenerative medicine to develop innovative therapies that enhance regeneration, retrieving original tissue properties. Multipotent Mesenchymal Stem/Stromal Cells (MSCs) have been successfully used to develop therapeutic products, as they secrete a variety of bioactive molecules that play a pivotal role in tissue regeneration. These factors are released in culture media for producing a conditioned medium (CM). The aforementioned assumptions led to the formulation of equine synovial membrane MSCs (eSM-MSCs)-the cellular pool that naturally regenerates joint tissue-combined with a medium enriched in immunomodulatory factors (among other bioactive factors) produced by umbilical cord stroma-derived MSCs (eUC-MSCs) that naturally contribute to suppressing the immune rejection in the maternal-fetal barrier. A description of an equine sport horse diagnosed with acute tarsocrural desmitis and treated with this formulation is presented. Ultrasonographic ligament recovery occurred in a reduced time frame, reducing stoppage time and allowing for the horse's return to unrestricted competition after the completion of a physical rehabilitation program. This study focused on the description of the therapeutic formulation and potential in an equine desmitis treatment using the cells themselves and their secretomes.

Rapamycin insensitive regulation of engineered ligament structure and function by IGF-1.

Following rupture, the anterior cruciate ligament (ACL) will not heal and therefore more than 400,000 surgical repairs are performed annually. Ligament engineering is one way to meet the increasing need for donor tissue to replace the native ligament; however, currently these tissues are too weak for this purpose. Treating engineered human ligaments with insulin-like growth factor-1 (IGF-1) improves the structure and function of these grafts. Since the anabolic effects of IGF-1 are largely mediated by rapamycin complex I (mTORC1), we used rapamycin to determine whether mTORC1 was necessary for the improvement in collagen content and mechanics of engineered ligaments. The effect of IGF-1 and rapamycin was determined independently and interactions between the two treatments were tested. Grafts were treated for 6 days before mechanical testing and analysis of collagen content. Following 8 days of treatment, mechanical properties increased 34% with IGF-1 and decreased 24.5% with rapamycin. Similarly, collagen content increased 63% with IGF-1 and decreased 36% with rapamycin. Interestingly, there was no interaction between IGF-1 and rapamycin, suggesting that IGF-1 was working in a largely mTORC1-independent manner. Acute treatment with IGF-1 did not alter procollagen synthesis in growth media, even though rapamycin decreased procollagen 55%. IGF-1 decreased collagen degradation 15%, whereas rapamycin increased collagen degradation 10%. Once again, there was no interaction between IGF-1 and rapamycin on collagen degradation. Together, these data suggest that growth factor-dependent increases in collagen synthesis are dependent on mTORC1 activity; however, IGF-1 improves human-engineered ligament mechanics and collagen content by decreasing collagen degradation in a rapamycin-independent manner. How the anticatabolic effects of IGF-1 are regulated have yet to be determined.NEW & NOTEWORTHY IGF-1 increases and rapamycin decreases mechanical and material properties of engineered human ligaments by regulating collagen content and concentration. There was no interaction between IGF-1 and rapamycin, suggesting that IGF-1 and rapamycin work independently. We found that IGF-1 improves collagen content by decreasing collagen degradation in a rapamycin-independent manner, whereas growth factor-dependent increases in collagen synthesis are blocked by rapamycin. These data may explain why interventions to increase IGF-1 have not helped rehabilitation.

Orthobiologic Interventions for Muscle Injuries.

Muscle injuries represent a common problem in active populations. Orthobiologics continue to be studied for their ability to improve muscle healing. To date, the basic science research for treating muscle injuries with platelet-rich plasma or stem cell remains novel. Furthermore, there are even fewer clinical studies on these topics, and their findings are inconclusive. Reviewing the literature, muscle injuries treated with ultrasound-guided leukocyte-rich PRP injections appear to have the strongest evidence. Scar formation remains a major barrier in muscle injury healing, and there is optimism for future orthobiologic treatments that target the downregulation of TGF-B, resulting in decreased scar development.

A Comparison of Intra-Articular Blood Cell Secretome and Blood Cell Secretome with Triamcinolone Acetonide in Dogs with Osteoarthritis: A Crossover Study.

Osteoarthritis (OA) is a growing welfare problem for dogs and a challenge to manage for the clinician, and most therapeutic options aim to control pain. In a randomized, double-blinded, placebo-controlled, 2-way, 2-period crossover study, we aimed to evaluate the use of Blood Cell Secretome (BCS) administrated intra-articularly, with or without the combination with triamcinolone, in dogs with bilateral hip OA. BCS is an acellular orthobiologic containing anti-inflammatory and anabolic proteins produced from the patient's own blood through extended coagulation in a defined environment. Fifteen dogs were initially assigned to a BCS group (BCSG, n = 5), a triamcinolone group (TG, n = 5), or a combination group (BCS+TG, n = 5). All had bilateral hip OA. After a 180-day follow-up, the crossover was performed with BCSG (n = 7) and BCS+TG (n = 7). BCSG received a single intra-articular administration of 3 mL of Blood Cell Secretome, and BCS+TG received BCS plus 0.5 mL of triamcinolone acetonide (40 mg/mL). The volume in BCSG was corrected to 3.5 mL with saline. In all patients, both hips were treated. For treatment follow-up, a copy of the Canine Brief Pain Inventory (divided into pain interference score­PIS and Pain Severity Score­PSS), Liverpool Osteoarthritis in Dogs (LOAD), and Canine Orthopedic Index (COI, divided into function, gait, stiffness, and quality of life) was completed on days 0, 8, 15, 30, 60, 90, 120, 150, and 180. Results were analyzed with the Mann−Whitney U test, effect size, and Kaplan−Meier estimators, followed by the log-rank test. p was set at <0.05. Patients of the sample had a mean age of 9.6 ± 2.9 years and a body weight of 29.2 ± 3.9 kg. Seven hips were classified as severe osteoarthritis, and eight were classified as moderate. No differences were found between groups at T0. Significant differences were observed in PSS scores at +8d, with BCS+TG exhibiting better results. PIS, PSS, LOAD, stiffness, and function scores were also lower in BCS+TG from +15 to +60d. The two groups showed similar improvements from +90 to +120d. Kaplan−Meier estimators showed that dogs in BCS+TG showed clinically-important differences for longer, despite a positive result in BCSG. The intra-articular administration of BCS alone was able to improve the overall condition of OA patients. Its combined use with triamcinolone acetonide lead to a faster and longer-lasting improvement in pain scores.

Developing Porous Ortho- and Pyrophosphate-Containing Glass Microspheres; Structural and Cytocompatibility Characterisation.

Phosphate-based glasses (PBGs) are promising materials for bone repair and regeneration as they can be formulated to be compositionally similar to the inorganic components of bone. Alterations to the PBG formulation can be used to tailor their degradation rates and subsequent release of biotherapeutic ions to induce cellular responses, such as osteogenesis. In this work, novel invert-PBGs in the series xP2O5·(56 - x)CaO·24MgO·20Na2O (mol%), where x is 40, 35, 32.5 and 30 were formulated to contain pyro (Q1) and orthophosphate (Q0) species. These PBGs were processed into highly porous microspheres (PMS) via flame spheroidisation, with ~68% to 75% porosity levels. Compositional and structural analysis using EDX and 31P-MAS NMR revealed that significant depolymerisation occurred with reducing phosphate content which increased further when PBGs were processed into PMS. A decrease from 50% to 0% in Q2 species and an increase from 6% to 35% in Q0 species was observed for the PMS when the phosphate content decreased from 40 to 30 mol%. Ion release studies also revealed up to a four-fold decrease in cations and an eight-fold decrease in phosphate anions released with decreasing phosphate content. In vitro bioactivity studies revealed that the orthophosphate-rich PMS had favourable bioactivity responses after 28 days of immersion in simulated body fluid (SBF). Indirect and direct cell culture studies confirmed that the PMS were cytocompatible and supported cell growth and proliferation over 7 days of culture. The P30 PMS with ~65% pyro and ~35% ortho phosphate content revealed the most favourable properties and is suggested to be highly suitable for bone repair and regeneration, especially for orthobiologic applications owing to their highly porous morphology.

Adipose cellular injection in the treatment of an intrasubstance Achilles tendon defect: a case report.

Our patient presented with a 1-year history of right sided Achilles tendon pain and weakness due to partial intrasubstance tear. The injury was refractory to conservative treatment, leading to a trial injection of microfragmented adipose tissue. Progressive healing and improved function were documented on physical exam and sonographically at subsequent follow-up appointments. About 4 weeks following the injection, the patient was able to return to his regular activity level. At the 6 month follow-up appointment, the patient continued to be pain free and had resumed all prior activities without limitations. This case highlights the potential microfragmented adipose tissue has as a regenerative treatment modality for the management of partial Achilles tendon tears.

Human mesenchymal stromal cells release functional mitochondria in extracellular vesicles.

Cartilage and other skeletal soft tissues heal poorly after injury, in part due to their lack of vascularity and low metabolic rate. No pharmacologic approaches have proven effective in preventing chronic degenerative disease after joint injury. Mesenchymal stromal cells (MSCs) have been investigated for their ability to treat pain associated with osteoarthritis (OA) and preserve articular cartilage. Limitations of MSCs include variability in cell phenotype, low engraftment and retention rates, and inconsistent clinical outcomes. Therefore, acellular biologic therapies such as extracellular vesicles (EVs) are currently being investigated. MSC-derived EVs have been found to replicate many of the therapeutic effects of their cells of origin, but the mechanisms driving this remain unclear. Recent evidence in non-orthopedic tissues suggests MSCs can rescue injured cells by donating mitochondria, restoring mitochondrial function in recipient cells, preserving cell viability, and promoting tissue repair. Our group hypothesized that MSCs package mitochondria for export into EVs, and that these so-called "mitoEVs" could provide a delivery strategy for cell-free mitochondria-targeted therapy. Therefore, the goals of this study were to: 1) characterize the vesicle fractions of the MSCs secretome with respect to mitochondrial cargoes, 2) determine if MSC-EVs contain functional mitochondria, and 3) determine if chondrocytes can take up MSC-derived mitoEVs. We isolated exosome, microvesicle, and vesicle-free fractions from MSC-conditioned media. Using a combination of dynamic light scattering and nanoparticle tracking, we determined that MSC-EV populations fall within the three size categories typically used to classify EVs (exosomes, microvesicles, apoptotic bodies). Fluorescent nanoparticle tracking, immunoblotting, and flow cytometry revealed that mitochondrial cargoes are abundant across all EV size populations, and mitoEVs are nearly ubiquitous among the largest EVs. Polarization staining indicated a subset of mitoEVs contain functional mitochondria. Finally, flow cytometry and fluorescent imaging confirmed uptake of mitoEVs by chondrocytes undergoing rotenone/antimycin-induced mitochondrial dysfunction. These data indicate that MSCs package intact, functional mitochondria into EVs, which can be transferred to chondrocytes in the absence of direct cell-cell interactions. This work suggests intercellular transfer of healthy MT to chondrocytes could represent a new, acellular approach to augment mitochondrial content and function in poorly-healing avascular skeletal soft tissues.

Human Osteochondral Explants as an Ex Vivo Model of Osteoarthritis for the Assessment of a Novel Class of Orthobiologics.

Osteoarthritis (OA) is a highly prevalent joint disease still lacking effective treatments. Its multifactorial etiology hampers the development of relevant preclinical models to evaluate innovative therapeutic solutions. In the last decade, the potential of Mesenchymal Stem Cell (MSC) secretome, or conditioned medium (CM), has emerged as an alternative to cell therapy. Here, we investigated the effects of the CM from adipose MSCs (ASCs), accounting for both soluble factors and extracellular vesicles, on human osteochondral explants. Biopsies, isolated from total knee replacement surgery, were cultured without additional treatment or with the CM from 106 ASCs, both in the absence and in the presence of 10 ng/mL TNFα. Tissue viability and several OA-related hallmarks were monitored at 1, 3 and 6 days. Specimen viability was maintained over culture. After 3 days, TNFα induced the enhancement of matrix metalloproteinase activity and glycosaminoglycan release, both efficiently counteracted by CM. The screening of inflammatory lipids, proteases and cytokines outlined interesting modulations, driving the attention to new players in the OA process. Here, we confirmed the promising beneficial action of ASC secretome in the OA context and profiled several bioactive factors involved in its progression, in the perspective of accelerating an answer to its unmet clinical needs.

The role of Platelet Rich Plasma and other orthobiologics in bone healing and fracture management: A systematic review.

BACKGROUND: Treatment of large bone defects and fracture healing complications (delayed and non-union) presents a substantial challenge for orthopaedic surgeons. Given that bone healing requires mechanical stability as well as a favourable biological microenvironment, orthobiologics such as Platelet-Rich Plasma (PRP) may have a significant clinical role to play. AIMS: To perform a systematic review of the available literature to assess the clinical effect of PRP, with or without other orthobiologics, on bone healing. METHOD: Two independent reviewers performed the literature search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical studies of any evidence, assessing effect of PRP with or without other orthobiologics on bone healing, were included. A qualitative analysis was carried out on the clinical and radiological outcomes reported. RESULT: 27 articles with 1631 patients (mean age = 43.56, 57.1% male, mean follow-up = 17.27 months) were included in the qualitative. Of the 27 studies, 13 dealt with fracture complications (delayed or non-unions), 7 with acute fracture healing, 4 with tibial osteotomies and lengthening procedures and 3 with lumbar spine pathology. 18/27 studies showed a clinical benefit of PRP, 8/27 showed no significant effect, and 1/27 showed a worse outcome with PRP. CONCLUSION: Our review suggests PRP may play a clinical role in bone healing but further randomised controlled trials (RCTs) using standardised outcomes should be performed to establish its efficacy.

Human Amniotic Suspension Allograft Improves Pain and Function in Knee Osteoarthritis: A Prospective Not Randomized Clinical Pilot Study.

Osteoarthritis (OA) is a chronic debilitating disorder causing pain and gradual degeneration of joints. Among various cell therapies, mesenchymal stem cell (MSC) therapy appears to provide encouraging results. Human amniotic suspension allografts (HASA) have anti-inflammatory and chondroregenerative potential and represent a promising treatment strategy. The purpose of the present study was to prospectively assess the safety, clinical effectiveness, and feasibility of intra-articular injections of human amniotic suspension allograft (HASA) in unilateral knee OA in order to assess the improvement of symptoms and delay the necessity for invasive surgical procedures. A total of 25 symptomatic patients, affected by knee OA were treated with 3 mL of HASA. Clinical evaluations before the treatment and after 3, 6, and 12 months were performed through International Knee Documentation Committee (IKDC) score and Visual Analogue Scale (VAS) scores. Adverse events were recorded. No severe complications were noted during the treatment and the follow-up period. A statistically significant improvement from basal evaluation to the 3-, 6-, and 12-month follow-up visits was observed. The present pilot study indicates that a single intra-articular injection of HASA seems safe and able to provide positive clinical outcomes, potentially offering a new minimally invasive therapeutic option for patients with knee OA.

Platelet-Rich Plasma as an Orthobiologic: Clinically Relevant Considerations.

Platelet-rich plasma (PRP) is an autologous blood-derived product processed to concentrate platelets and the associated growth factors. PRP has been shown to be relatively well-tolerated and safe to use for a number of conditions in humans, equines, and canines. There are multiple commercial systems that have been validated for canine use. These systems use a variety of methodologies to produce a PRP product. However, PRP products have been shown to differ greatly between systems. Further study is needed to fully elucidate optimal component concentrations for various indications.

Evaluation of Autologous Protein Solution Injection for Treatment of Superficial Digital Flexor Tendonitis in an Equine Model.

Autologous protein solution (APS) has been used anecdotally for intralesional treatment of tendon and ligament injuries, however, its use in these injuries has never been studied in vivo. Our objective was to evaluate the effect of APS on tendon healing in an equine superficial digital flexor (SDF) tendonitis model. We hypothesized intralesional injection of APS would result in superior structural and biomechanical healing. SDF tendonitis was induced in both forelimbs of eight horses using collagenase injection. One forelimb was randomly assigned to receive an intralesional injection of APS, while the other was injected with saline. Ultrasonographic examinations were performed at weeks -1, 0, 2, 4, 8, and 12 following treatment. At 12 weeks, horses were euthanized and SDF samples harvested. Histologic evaluation, biomechanical testing, gene expression analysis, total glycosaminoglycan (GAG) and total DNA quantification were performed. Collagen type III (COL3A1) expression was significantly higher (p = 0.028) in saline treated tendon than in normal tendon. Otherwise, there were no significant differences in gene expression. There were no significant differences in histologic or ultrasonographic scores between groups. Mean total DNA content was significantly higher (p = 0.024) in saline treated tendons than normal tendons, whereas total DNA content was not significantly different between APS treated tendon and normal tendon. Elastic modulus was higher in APS treated than saline treated tendon, but the difference was not significant. Reduced expression of COL3A1 in APS treated tendon may indicate superior healing. Increased total DNA content in saline treated tendon may indicate ongoing healing processes, vs. APS treated tendons which may be in the later stages of healing. Limitations include a relatively short study period and inconsistency in size and severity of induced lesions. Intralesional injection of APS resulted in some improvements in healing characteristics.

Gluing Living Bone Using a Biomimetic Bioadhesive: From Initial Cut to Final Healing.

Osteoporotic fractures are a growing issue due to the increasing incidence of osteoporosis worldwide. High reoperation rates in osteoporotic fractures call for investigation into new methods in improving fixation of osteoporotic bones. In the present study, the strength of a recently developed bone bioadhesive, OsStictm, was evaluated in vivo using a novel bone core assay in a murine animal model at 0, 3, 7, 14, 28, and 42 days. Histology and micro-CT were obtained at all time points, and the mean peak pull-out force was assessed on days 0-28. The adhesive provided immediate fixation to the bone core. The mean peak bone core pull-out force gradually decreased from 6.09 N (σ 1.77 N) at day 0 to a minimum of 3.09 N (σ 1.08 N) at day 7, recovering to 6.37 N (σ 4.18 N) by day 28. The corresponding fibrin (Tisseel) control mean peak bone core pull-out characteristic was 0.27 N (σ 0.27 N) at day 0, with an abrupt increase from 0.37 N (σ 0.28) at day 3, 6.39 N (σ 5.09 N) at day 7, and continuing to increase to 11.34 N (σ 6.5 N) by day 28. The bone cores failed either through core pull-out or by the cancellous part of the core fracturing. Overall, the adhesive does not interrupt healing with pathological changes or rapid resorption. Initially, the adhesive bonded the bone core to the femur, and over time, the adhesive was replaced by a vascularised bone of equivalent quality and quantity to the original bone. At the 42 day time point, 70% of the adhesive in the cancellous compartment and 50% in the cortical compartment had been replaced. The adhesive outwith the bone shell was metabolized by cells that are only removing the material excess with no ectopic bone formation. It is concluded that the adhesive is not a physical and biochemical barrier as the bone heals through the adhesive and is replaced by a normal bone tissue. This adhesive composition meets many of the clinical unmet needs expressed in the literature, and may, after further preclinical assessments, have potential in the repair of bone and osteochondral fragments.

Use of Bone Marrow Concentrate to Treat Pain and Musculoskeletal Disorders: An Academic Delphi Investigation.

BACKGROUND: Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. OBJECTIVES: The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. STUDY DESIGN: Delphi panel technique. SETTING: The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. METHODS: An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. RESULTS: Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. LIMITATIONS: The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. CONCLUSIONS: There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.