Biological Adjuvants Research Articles

Biologic Augmentation of Rotator Cuff Repair: Current Concepts Review.

Rotator cuff tears are common in an aging population. Thus far, primary repairs have shown high re-tear rates suggesting the need for improved healing modalities. Current augmentations of rotator cuff repairs include synthetic and biological scaffolds, surgical bone marrow venting, and infusing the repair with a variety of stem cells and growth factors aimed at restoring the native cellular structure and function of the repaired tissue. This current concepts review discusses the anatomy, physical presentation, diagnosis, and treatment of rotator cuff tears; biological adjuvants for rotator cuff repairs; and the current literature on outcomes after biologically augmented rotator cuff repairs. [Orthopedics. 202x;4x(x):xx-xx.].

Protection efficacy and immunogenicity of Clostridium chauvoei proteins as a subunit blackleg vaccine or an adjuvant for Clostridium perfringens epsilon toxoid

Potential application of Clostridium chauvoei proteins was studied as a subunit blackleg vaccine or a biological adjuvant for Clostridium perfringens epsilon toxoid vaccine. Extracellular and cell surface proteins were extracted from C. chauvoei culture, and their protective efficacy was evaluated by potency test in guinea pigs. In order to investigate the effect of cell surface proteins on C. perfringens epsilon toxoid immunogenicity, rabbits were inoculated subcutaneously twice with: C. perfringens type D toxoid supernatant + 200 μg C. chauvoei cell surface proteins (PR-200), toxoid supernatant + 400 μg cell surface proteins (PR-400), inactivated C. perfringens type D vaccine (Vac), toxoid supernatant (Tox), or PBS. Isolation of cell surface proteins yielded about 2.5 mg/L culture protein with a sharp band at 43 kDa probably corresponding to flagellin. Potency test demonstrated the protection ability of both cellular and extracellular proteins of C. chauvoei. ELISA showed that the highest antibody titers against epsilon toxoid belonged to PR-400 and Vac groups. The effect of days post immunization on antibody response was not significant. No significant difference was observed between PR-400 and Vac, as well as PR-200 and Tox groups. Clostridium chauvoei cell surface proteins may have the potential for application as a blackleg disease vaccine and an adjuvant for clostridial toxoids.

Biologic Adjuvants to Rotator Cuff Repairs Induce Anti-inflammatory Macrophage 2 Polarization and Reduce Inflammatory Macrophage 1 Polarization In Vitro

PurposeTo examine the effect of various biologic adjuvants on the polarization of macrophages in an in vitro model for rotator cuff tears. MethodsTissue was harvested from 6 patients undergoing arthroscopic rotator cuff repair. An in vitro model of the supraspinatus and subacromial bursa was created and treated with control, platelet rich plasma (PRP), autologous activated serum (AAS), or a combination of PRP+AAS. The effect of treatment on macrophage polarization between M1 pro-inflammatory macrophages or M2 anti-inflammatory macrophages was measured using gene expression, protein expression, flow cytometry and nitric oxide (NO) production. ResultsTendon and bursa treated with PRP, AAS and PRP+AAS significantly decreased the gene expression of M1 markers IL-12 and TNF-a, while significantly increasing the expression of M2 markers Arginase, IL-10 and TGF-b (p<0.05) compared to treatment with control. ELISA analysis of protein production demonstrated that compared to control, co-culture treated with PRP, AAS and PRP+AAS significantly decreased markers of M1-macrophages (IL-6, IL-12, and TNF-a), while significantly increasing the expression of markers of M2-macrophages (Arginase, IL-10, and TGF-b) (p<0.05). Flow cytometry analysis of surface markers demonstrated that compared to control, tendon and bursa treated with PRP, AAS and PRP+AAS significantly decreased markers of M1-macrophages (CD80, CD86, CD64, CD16), while significantly increasing the expression of markers of M2-macrophages (CD163 and CD206) (p<0.05). Treatment of the co-culture with PRP, AAS and PRP+AAS consistently demonstrated a decrease in NO production (p<0.05) compared to control. AAS and PRP+AAS demonstrated an increased macrophage shift to M2 compared to PRP alone, whereas there was not as uniform of a shift when comparing PRP+AAS to AAS alone. ConclusionsIn an in vitro model of rotator cuff tears, the treatment of supraspinatus tendon and subacromial bursa with PRP, AAS and PRP+AAS demonstrated an increase in markers of anti-inflammatory M2-macrophages and a concomitant decrease in markers of pro-inflammatory M1-macrophages. AAS and PRP+AAS contributed to a large shift to macrophage polarization to the anti-inflammatory M2 compared to PRP.

The treatment of Canine Parvovirus and the vaccine improve

Canine Parvovirus (CPV) is common in dogs, with 50% of dogs infected with CPV and 80% of affected dogs likely to die. The main cause of death was myocarditis or enteritis caused by canine parvovirus. However, there is currently no good treatment for CPV infection, only vaccination can prevent it in advance. When dogs receive the inactivated vaccine, the mortality rate can be reduced to 1.25%. At present, there are several methods to treat canine parvovirus, such as inactivated vaccine, attenuated vaccine, gene vaccine and so on. The popular prevent of CPV is to inoculated pentavaccine, a kind of inactivated vaccine. But it needs to inoculated twice. So now, scientist focus on to invent genetic engineering vaccine, that use CPV-2, the DNA of CPV to invent a kind of DNA vaccine, its simple operation and efficient expression of antigen proteins, and some vectors can also be used as biological adjuvants to enhance the immune effect, which are unmatched by traditional vaccines. Inoculated Penta vaccine is the most popular way to prevent CPV but DNA vaccine will become the best way to prevent CPV virus. This paper introduces the vaccine can be used available for Canine parvovirus.

A Novel Application of Neural Networks to Identify Potentially Effective Combinations of Biologic Factors for Enhancement of Bone Fusion/Repair

Category: Basic Sciences/Biologics; Other Introduction/Purpose: The use of biologic adjuvants (orthobiologics) is becoming commonplace in orthopaedic surgery. Amongst other applications, biologics are often added to enhance fusion rates in spinal surgery and to promote bone healing in complex fracture patterns. Generally, orthopaedic surgeons use only one biomolecular agent (ie allograft with embedded bone morphogenic protein-2) rather than several agents acting in concert. Bone fusion, however, is a highly multifactorial process and it likely could be more effectively enhanced using biologic factors in combination, acting synergistically. We used artificial neural networks to identify combinations of orthobiologic factors that potentially would be more effective than single agents. Methods: Available data on the outcomes associated with various orthopaedic biologic agents, electrical stimulation, and pulsed ultrasound were curated from the literature and assembled into a form suitable for machine learning. The best among many different types of neural networks was chosen for its ability to generalize over this dataset, and that network was used to make predictions concerning the expected efficacy of 2400 medically feasible combinations of 9 different agents and treatments. Results: The most effective combinations were high in the bone-morphogenic proteins (BMP) 2 and 7 (BMP2, 15mg; BMP7, 5mg), and in osteogenin (150ug). Some of the most effective combinations included bone marrow aspirate concentrate. In some others, electrical stimulation could substitute for osteogenin. BMP2 and BMP7 appear to have the strongest pairwise linkage of the factors analyzed in this study. Conclusion: Artificial neural networks are powerful forms of artificial intelligence that can be applied readily in the orthopeadic domain, but neural network predictions improve along with the amount of data available to train them. This study provides a starting point from which networks trained on future, expanded datasets can be developed. Yet even this initial model makes specific predictions concerning potentially effective combinatorial therapeutics that should be verified experimentally. Furthermore, our analysis provides an avenue for further research into the basic science of bone healing by demonstrating agents that appear to be linked in function.

Retrospective Outcome Analysis of Allogenic Bone Graft

Bone bank has become an essential requirement for centers that perform tumor and reconstructive surgeries. It provides allogenic bone procured from cadavers as well as live donors in the form of surgical residues. Thus, we conducted a retrospective observational study on recipients who underwent various reconstructive procedures using fresh frozen allograft obtsined from the live donors through surgical residues in a newly established bone bank. The outcomes of cases operated where allogenic bone grafts were used between January 2018 and November 2020 were analyzed in terms of infection and time taken for the grafts to incorporate, allowing weight-bearing in the lower limbs. A total of 223 grafts were obtained as surgical residues from replacement surgeries and traumatic amputations performed on non-salvageable limbs. Out of these, 70 grafts were transplanted into eligible recipients, who were followed up for at least one year. Among the 70 recipients, 15 were lost to follow-up. The outcome data of the remaining 55 recipients was tabulated, including infections (early, delayed and late) and the achievement of weight-bearing milestones when transplanted in lower limbs. Out of the 55 cases, allografts were used alone in 20 cases, while in 35 cases, they were augmented by implants or cement. Two cases (3.6%) experienced acute infections, and another two cases (3.6%) had chronic infection. The mean time for weight-bearing was found to be 7 months when used alone and 3.5 months when augmented with cement or an implant. Additionally, five patients did not show complete integration of the graft. The results of using allogenic bone graft are quite encouraging, suggesting their potential as biological adjuvants in reconstructive surgeries.

Clinical Performance and Outcomes of an Injectable Bone Graft Substitute Following Core Decompression during the Treatment of Osteonecrosis of the Femoral Head

AbstractOsteonecrosis of the femoral head (ONFH) can be challenging to manage, as it primarily affects younger adult patients. Hip preservation is preferred in this population, and there is a heightened focus on treatment strategies such as biologic adjuvants and bone grafting. Therefore, the objective of this systematic literature review was to evaluate the clinical performance of a commercially available injectable bone graft substitute (calcium sulfate [CaSO4]/calcium phosphate [CaPO4]; Pro-Dense, Wright Medical Technology Inc., Memphis, TN) following core decompression for the management of ONFH. Specifically, we aimed to examine (1) patient-reported outcomes, (2) progression of disease, (3) rate of revision, and (4) complications. A systematic literature review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses, using PubMed, Google Scholar, and Cochrane Library in July 2020 (gap search conducted in March 2022). The review included all clinical studies, published in English, on the use of an injectable bone graft substitute in ONFH-related procedures since 2007. Meta-analysis was conducted on Harris Hip Score (HHS), Visual Analog Scale (VAS), progression of disease, rate of revision, and complications. Nine studies were identified, with a total of 390 subjects ranging in age from 15 to 70 (weighted mean = 40.4) years old, with a weighted mean follow-up time of 37.1 months. Weighted mean improvement in HHS was +17.5 points (n = 296 procedures), while weighted mean improvement in VAS score was –3.0 points (n = 188 procedures). Overall weighted progression of disease for all patients was 6.1% (n = 17.9), including studies reporting precollapse (5.9%; n = 9.1/155) and/or postcollapse (9.91%; n = 16/162) lesions. Overall weighted revision rate was 2.9% (n = 11.5/390), including studies reporting precollapse (3.2%; n = 7.7/239) and/or postcollapse (4.3%; n = 8.2/191) lesions. The minor complication rate was 1.02% (n = 3/293), with no major complications reported. Clinical evidence on injectable CaSO4/CaPO4 bone graft substitute supports an acceptable benefit–risk profile, including safe real-world use since 2007, following core decompression for the treatment of ONFH.

Current Concepts in Clinical Treatment of Osteochondral Lesions of the Talus

Osteochondral lesions of the talus (OLTs) are common reason for the deep ankle pain and seriously affect patient’s sports and the daily life. Managements of the OLTs including conservative treatment, cartilage repair surgery, cartilage replacement surgery and cartilage regeneration surgery. For asymptomatic, serendipitous, or acute OLTs with no displaced fragments, conservative treating is suitable to execute, including mainly including affected ankle immobilization with or without physical therapy, bone stimulation, or drugs used. For small OLTs, cartilage repair strategy like bone marrow stimulation technique (BMS) was recommended, and microfracture is the most commonly used surgical procedure. For larger OLTs, both cartilage replacement and cartilage regeneration could be considered including. Although there are many treatment options, each treatment option may have certain limitations and may not be applicable. With the continuous development of science and technology, the development of biological adjuvants and tissue engineering technology has been accelerated and promoted. The combined application of surgery and biological adjuvants and tissue engineering technology has gradually become a hot spot in clinical research. This work briefly introduced present strategies and advance in treatment of OLTs and discussed the potential application problems aiming to provide reference for the future treatment selection and research of OLTs.

Development and Evaluation of the Biological Adjuvant Bivalent Vaccine for Preventing Newcastle Disease and Infectious Bursal Disease

Newcastle disease (ND) and infectious bursal disease (IBD) are both one of the most economically important infectious diseases, which cause high infection rate and mortality of chickens and restrict the development of the poultry industry. Currently, vaccination is the most effective method to prevent ND and IBD. In this study, the biological adjuvant bivalent vaccine (rClone30-VP2L-chGM-CSF) was developed for preventing ND and IBD. Furthermore, the immune and protective effects of rClone30-VP2L-chGM-CSF were evaluated in specific-pathogen-free chickens. The experimental results indicated that chickens immunized with rClone30-VP2L-chGM-CSF vaccine significantly improved anti-IBDV and anti-NDV antibody titer; the level of CD4+ T, CD8+ T, B+, MHC-II+, and monocyte/macrophagocyte+ cells; the concentrations of IL-1β, IL-4, IL-17, IFN-α, IFN-β, and IFN-γ; and the splenocyte proliferation rate. Anti-NDV antibody titer reached the theoretical protection value of 4log2 at 7 days after immunization in chickens of rClone30-VP2L-chGM-CSF group; however, which at 14 days after immunization in chickens of rClone30-VP2L and rClone30. These results showed that chickens immunized with rClone30-VP2L-chGM-CSF stimulated stronger immune response than those with the rClone30-VP2L and rClone30. Chickens were challenged with virulent IBDV BC6/85, which were protected in the rClone30-VP2L-chGM-CSF group. Furthermore, IBDV RNA was not measured, and there appeared to be little apoptosis in the bursa of Fabricius in the rClone30-VP2L-chGM-CSF group. Therefore, rClone30-VP2L-chGM-CSF is a promising vaccine candidate against infectious bursal disease virus (IBDV) and newcastle disease virus (NDV), and it provides an idea for developing other poultry vaccines.

Designing a bioadjuvant candidate vaccine targeting infectious bursal disease virus (IBDV) using viral VP2 fusion and chicken IL-2 antigenic epitope: A bioinformatics approach

Infectious Bursal Disease (IBD) is a common and contagious viral infection that significantly affects the poultry industry. This severely suppresses the immune system in chickens, thereby threating their health and well-being. Vaccination is the most effective strategy for preventing and controlling this infectious agent. The development of VP2-based DNA vaccines combined with biological adjuvants has recently received considerable attention due to their effectiveness in eliciting both humoral and cellular immune responses. In this study, we applied bioinformatics tools to design a fused bioadjuvant candidate vaccine from the full-length sequence of the VP2 protein of IBDV isolated in Iran using the antigenic epitope of chicken IL-2 (chiIL-2). Furthermore, to improve the antigenic epitope presentation and to maintain the three-dimensional structure of the chimeric gene construct, the P2A linker (L) was used to fuse the two fragments.Our in-silico analysis for the design of a candidate vaccine indicates that a continuous sequence of amino acid residues ranging from 105 to 129 in chiIL-2 is proposed as a B cell epitope by epitope prediction servers. The final 3D structure of the VP2-L-chiIL-2105-129 was subjected to physicochemical property determination, molecular dynamic simulation, and antigenic site determination. The results of these analyses led to the development of a stable candidate vaccine that is non-allergenic and has the potential for antigenic surface display potential and adjuvant activity. Finally, it is necessary to investigate the immune response induced by our proposed vaccine in avian hosts. Notably, increasing the immunogenicity of DNA vaccines can be achieved by combining antigenic proteins with molecular adjuvants using the principle of rational vaccine design.

Rethinking Cartilage Lesions of the Ankle: An Update on the Role of Biologic Adjuvants.

Osteochondral lesions of the talus are common injuries in the ankle joint often resulting in early-onset osteoarthritis if left untreated. The avascular nature of articular cartilage limits healing capacity; therefore, surgical strategies are typically used in the treatment of these injuries. These treatments often result in the production of fibrocartilage rather than the native hyaline cartilage, which has decreased mechanical and tribological properties. Strategies to improve the ability of fibrocartilage to be more hyaline-like and thus more mechanically robust have been widely investigated. Biologic augmentation, including concentrated bone marrow aspirate, platelet-rich plasma, hyaluronic acid, and micronized adipose tissue, has been used in the augmentation of cartilage healing, with studies demonstrating promise. This article provides an overview and update on the various biologic adjuvants used in the treatment of cartilage injuries in the ankle joint.

Особенности хирургического лечения макулярного отверстия с атипичной эпиретинальной тканью: серия клинических случаев

Purpose. To present the surgical features of successful repair of macular hole with atypical epiretinal proliferation. Material and methods. A retrospective analysis of the treatment of 4 patients with macular hole-associated epiretinal proliferation. All patients underwent a preoperative examination – a standard ophthalmological examination, optical coherence tomography of the macular area with hole diameter measurement, confirmation of the presence of epiretinal tissue. Surgery consisted of the stages: vitrectomy, staining of the epiretinal tissue, its careful exfoliation with end-griping forceps, cutting off the floating part by a vitrector using «shaving» mode and preserving the remnants of the tissue around the edges of the hole, finishing with air tamponade. During the postoperative period the patient followed the «face down» position continuously for 3 hours. Results. In all cases the best corrected visual acuity (BCVA) increased and closure of the macular hole was achieved. Conclusions. 1. Surgical treatment of a macular hole with atypical epiretinal tissue has specific features that are not characteristic of the traditional treatment of an idiopathic macular hole. 2. The presence of a fixed perifoveal border of epiretinal tissue is an intraoperative feature. 3. Preservation of the perifoveolar border of epiretinal proliferation contributes to the closure of the macular hole without any additional mechanical manipulations or the use of biological adjuvants. 4. For a better understanding of the regenerative properties of epiretinal proliferation, it is necessary to increase the study sample, as well as to conduct histological studies of this tissue. Keywords: macular hole, epiretinal proliferation, atypical tissue, yellow tissue, perifovea corona phenomenon

A protein-based subunit vaccine with biological adjuvants provides effective protection against Pasteurella multocida in pigs

Streptococcus suis (S. suis) and Pasteurella multocida (P. multocida) are pathogens that can cause zoonotic diseases. P. multocida toxin (PMT) is an important virulence factor that causes atrophic rhinitis in pigs. Suilysin (Sly) is an extracellular protein of S. suis and has been shown to be a potential adjuvant. Previous studies have indicated that subunit vaccines containing several fragments of PMT as antigens are safer than traditional inactivated or live-attenuated vaccines. However, protein-based vaccines need strong adjuvants to enhance their immunogenicity. In this study, recombinant PMT-NC (rPMT-NC) protein antigen was formulated with either recombinant Sly (rSly) or CpG oligodeoxynucleotides (CpG) as the adjuvant. The immune responses elicited by these vaccines and the protective efficacy after challenge with live P. multocida were evaluated in piglets. In the dose-dependent test, piglets immunized with the low dose (100 µg) of rSly had increased antigen-specific total IgG, interferon (IFN)-γ gene expression, and CD4+ and CD8+ T-cell populations. Compared to piglets in the commercial (Al-gel) adjuvant and the control groups (p < 0.05), piglets in the biological adjuvant groups showed significantly reduced turbinate atrophy, nasal distortion, and lung lesion scores after challenge with P. multocida serotype A. Vaccines containing rSly or CpG adjuvant enhanced humoral and cellular immune responses and protection against P. multocida. This combination of a protein-based antigen formulated with a biological adjuvant showed synergistic and protective effects against atrophic rhinitis and has potential to be developed as part of a bivalent vaccine.

MESENCHYMAL CELLS IN ROTATOR CUFF REPAIR - TECHNIQUE DESCRIPTION AND CASE REPORTS.

To describe a protocol of obtention of mesenchymal stem cells and to report their use as a biological adjuvant in three patients undergoing arthroscopic rotator cuff repair. Case series of patients who underwent arthroscopic repair of isolated full-thickness supraspinatus tear using mesenchymal stem cells obtained from the bone marrow as a biological adjuvant. All patients were operated on at the same institution, by a surgeon with 13 years of experience. The cells were applied at the end of the procedure, at the tendon-bone interface, at an approximate concentration of 2,000,000 mesenchymal cells/mm3 and a total volume of 5 ml. All patients improved with the procedure, with one excellent and two good results. All cases overcame the minimally important clinical difference. All cases reached tendon healing, without partial or complete re-tears. We observed no complications. Arthroscopic rotator cuff repair with added mesenchymal cells obtained from bone marrow and submitted to a cell expansion process led to good functional results and healing in all cases in the sample, with no complications. Level of Evidence IV, Case Series.

Novel BC02 Compound Adjuvant Enhances Adaptive and Innate Immunity Induced by Recombinant Glycoprotein E of Varicella-Zoster Virus.

Both adaptive and innate immunity responses are necessary for the efficient elimination of different pathogens. However, the magnitude, quality and desired type of immune response specific to the co-administered antigen is largely determined by adjuvants. BC02 (BCG CpG DNA compound adjuvants system 02) is a novel compound adjuvant with independent intellectual properties, which is composed of BCG CpG DNA biological adjuvant with Al(OH)3 inorganic salt adjuvant acting as a delivery system. Its safety and strong adjuvant efficacy have been effectively verified in preclinical and clinical trials (Phase Ib, ClinicalTrials.gov Identifier: NCT04239313 and Phase II, ClinicalTrials.gov Identifier: NCT05284812). In this study, we report the level of cell-mediated immunity (CMI) and humoral immune response induced by the BC02 novel adjuvant combined with different doses of varicella-zoster virus (VZV) glycoprotein E (gE) in a mouse model. In addition, we conducted preliminary in vitro experiments to explore the enhancement of RAW264.7 cell immune activity by BC02 adjuvanted-gE experimental vaccine to activate innate immune response. The results showed that the BC02-adjuvanted low, medium or high dose of gE were highly effective in eliciting both CMI and humoral immune responses to the immunized mice, respectively. The production of gE-specific IFN-γ and IL-2-specific T cells was established within 28 days after booster immunization. In particular, the effect of BC02-adjuvanted medium dose of gE has been shown to be more prominent. Meanwhile, fluorescent antibody to membrane antigen (FAMA) and serum antibody plaque reduction tests have also shown that the BC02 adjuvanted-medium dose of gE antigen could induce the secretion of neutralizing antibodies against clinically isolated VZV strains in mice. In addition, our findings have shown that 1/25 dose of gE+BC02 medium dose experimental vaccine can significantly induce the secretion of innate immune cytokines TNF-A, MCP-1, IL-6 and GM-CSF and up-regulate the costimulatory molecules CD40, CD80 and I-A/I-E on RAW264.7 cells; and it has also been activated to form M2 macrophages. At the same time, RAW264.7 cells were stimulated for 12 h, and their phagocytosis was significantly enhanced. Taken together, these results suggest that the BC02 compound adjuvant offers a strategy to induce an appropriate innate and adaptive immunity against the different doses of the VZV gE protein to improve subunit vaccine efficacy, and BC02 may be a promising adjuvant candidate for subunit HZ vaccines.

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

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. 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. Cohort study; Level of evidence, 3. 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. 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). 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.

A novel application of neural networks to identify potentially effective combinations of biologic factors for enhancement of bone fusion/repair

The use of biologic adjuvants (orthobiologics) is becoming commonplace in orthopaedic surgery. Among other applications, biologics are often added to enhance fusion rates in spinal surgery and to promote bone healing in complex fracture patterns. Generally, orthopaedic surgeons use only one biomolecular agent (ie allograft with embedded bone morphogenic protein-2) rather than several agents acting in concert. Bone fusion, however, is a highly multifactorial process and it likely could be more effectively enhanced using biologic factors in combination, acting synergistically. We used artificial neural networks, trained via machine learning on experimental data on orthobiologic interventions and their outcomes, to identify combinations of orthobiologic factors that potentially would be more effective than single agents. This use of machine learning applied to orthobiologic interventions is unprecedented. Available data on the outcomes associated with various orthopaedic biologic agents, electrical stimulation, and pulsed ultrasound were curated from the literature and assembled into a form suitable for machine learning. The best among many different types of neural networks was chosen for its ability to generalize over this dataset, and that network was used to make predictions concerning the expected efficacy of 2400 medically feasible combinations of 9 different agents and treatments. The most effective combinations were high in the bone-morphogenic proteins (BMP) 2 and 7 (BMP2, 15mg; BMP7, 5mg), and in osteogenin (150ug). In some of the most effective combinations, electrical stimulation could substitute for osteogenin. Some other effective combinations also included bone marrow aspirate concentrate. BMP2 and BMP7 appear to have the strongest pairwise linkage of the factors analyzed in this study. Artificial neural networks are powerful forms of artificial intelligence that can be applied readily in the orthopaedic domain, but neural network predictions improve along with the amount of data available to train them. This study provides a starting point from which networks trained on future, expanded datasets can be developed. Yet even this initial model makes specific predictions concerning potentially effective combinatorial therapeutics that should be verified experimentally. Furthermore, our analysis provides an avenue for further research into the basic science of bone healing by demonstrating agents that appear to be linked in function.

Recombinant suilysin of Streptococcus suis enhances the protective efficacy of an engineered Pasteurella multocida toxin protein

Suilysin (Sly) from Streptococcus suis has been shown to elicit strong immune responses and may act as a vaccine adjuvant. In the present study, we tested the adjuvant effect of Sly using an engineered Pasteurella multocida toxin, rPMT-NC, as the antigen. The antigen was also formulated with other conventional adjuvants (aluminum hydroxide, water-in-oil-in-water) for comparison. The efficacy of these vaccine formulations were evaluated in mice. The optimal dosage of purified rSly for enhancing immune responses in mice was first determined to be 40 μg/ml based on significantly (p < 0.05) increased serum antibody titers, expression of cytokines, including interleukin (IL)-4, IL-12, and interferon (IFN)-γ and the survival rate after challenge with P. multocida. Mice immunized with rPMT-NC + rSly had augmented antibody production and cellular immunity compare to those immunized with rPMT-NC plus other adjuvants. In addition, the survival rate of mice immunized with rPMT-NC + rSly was the highest (70% v.s. 30% of mice immunized with rPMT-NC alone) among all groups. In conclusion, rSly has the potential to be used as a biological adjuvant to enhance immune responses and protective efficacy of protein-based vaccines.

Efficacy of Autologous Intra-articular Platelet Rich Plasma Injection as a Biological Adjuvant in Early Primary Osteoarthrosis Knee—A Prospective Study

Introduction Classical characteristics of osteoarthrosis are reduction or loss of articular cartilage, new bone formation, accompanied by synovial proliferation resulting in pain, loss of joint function, and disability. Platelet rich plasma (PRP) has been used to provide stimulus for local regeneration and healing. The present study was conducted with the aim of evaluating the clinical outcome and efficacy of injecting PRP intra-articularly in early primary osterarthrosis knee. Objective Prospective study was conducted with the aim of evaluating the clinical outcome of efficacy of injection of PRP in early primary osteoarthrosis knee with respect to pain, stiffness, function and quality of life, in short-term follow-up. Attempt was made to standardize protocol and formulate PRP. Materials and Methods Patients were divided into two groups: one treated with two autologous PRP injections at 2 weeks interval and second received symptomatic treatment with physiotherapy. Patients were prospectively evaluated at baseline and then at 1 month, 3 months, and 6 months of follow-up using the visual analog scale (VAS) score, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score, and range of movements. Results There was reduction in VAS score in group 1 patients compared with group 2 patients with the p-value &lt;0.0001 which was highly significant. There was a significant improvement in WOMAC score at 1 month, 3 months, and 6 months in group 1 compared with group 2 patients. Conclusion Autologous PRP in osteoarthrosis of knee has emerged as a simple technique, sensitive procedure, and cost-effective treatment option. Administration of intra-articular PRP injections reduced the VAS score significantly and also a significant improvement in the WOMAC score was observed in patients who were treated with PRP injection. The two doses of injection of PRP were found to give adequate relief in short term of 6 months and further long-term studies are required.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity.

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.