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1. NanoSUS (Ultra Fine Grained Stainless-Steel) for Percutaneous Spinal Injection

   Bahram Saleh, Caterina Bartomeu ( December 2019 , Tissue Engineering and Regenerative Medicine International Society) Start-up Competition, 2019)

   Vertebral augmentation, which includes vertebroplasty and kyphoplasty, is a minimally invasive procedure to relieve the back pain caused by vertebral compression fracture (VCF) and osteoporosis-related fractures. Vertebroplasty involves the introduction of a percutaneous needle into the vertebral body followed by an image-guided injection of cement directly into the vertebra. The market size for Vertebroplasty is expected to increase from $910 million in 2019, to $1500 million in 2024 with a CAGR of 8.4%, due to the growing demand by increasing geriatric population, rising incidence of spine illness and technological advancements in this field [1]. NanoSUS Bio-Tech (USA) was found based on a collaboration between Komatsuseiki Kosakusho Co., Ltd (Japan) and Northeastern University (NEU) in 2019 [2]. This company manufactures high strength ultra-fine-grained stainless steel with antimicrobial surface. However, nanoSUS has been developing ultra-fine-grained stainless steel since 2002 [3, 4]. Using this technology, we are able to control grain size without any change in chemical composition of commercially available FDA approved stainless steel. We are able to form this stainless steel into a vertebroplasty needle using our precision machining techniques at Komatsuseiki Kosakusho Co., Ltd. We believe this product will reduce the healthcare expenses for patients suffering from VCF due to its cost-effective manufacturing process and antimicrobial surface, which reduces iatrogenic infections and shortens hospitalization time. We are going to submit a funding proposal to Center for Disruptive Musculoskeletal Innovation (CDMI) that will aid to expand the collaboration between Komatsuseiki Kosakusho Co., Ltd and NEU. The company will be established by financing from Komatsuseiki Kosakusho Co., Ltd (Japan), in Boston, MA. It will manage the collaborations between academia, marketing consultants and lawyers in US, and directors and researchers in Japan. 

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2. Developing Bioactive-Nanograined Metals With Bacterial Biofilm Inhibition Properties For Orthopedic Devices

   Kelkar, Shaunak ; Saleh, Bahram ; Yusa, Fumie ; Suzuki, Yohei ; Komatsu, Takafumi ; Webster, Thomas ( January 2021 , Orthopaedic Research Society)

   null (Ed.)

   INTRODUCTION: Orthopedic implants are important therapeutic devices for the management of a wide range of orthopedic conditions. However, bacterial infections of orthopedic implants remain a major problem, and not an uncommon one, leading to an increased rate of osteomyelitis, sepsis, implant failure and dysfunction, etc. Treating these infections is more challenging as the causative organism protects itself by the production of a biofilm over the implant’s surface (1). Infections start by the adhesion and colonization of pathogenic bacteria such as Staphylococcus aureus (SA), Staphylococcus epidermidis (SE), Escherichia coli (E. coli), Methicillin-Resistant Staphylococcus aureus (MRSA), and Multi-Drug Resistant Escherichia coli (MDR E. coli) on the implant’s surfaces. Specifically, Staphylococcus comprises up to two-thirds of all pathogens involved in orthopedic implant infections (2). However, bacterial surface adhesion is a complex process influenced by several factors such as chemical composition, hydrophobicity, magnetization, surface charge, and surface roughness of the implant (3). Considering the intimate association between bacteria and the implant surface, we measured the effect of stainless-steel surface properties on bacterial surface attachment and subsequent formation of biofilms controlling above mentioned factors. METHODS: The prominent bacteria responsible for orthopedic implant infections (SA, SE, E. coli, MRSA, and MDR E. coli) were used in this study. We were able to control the grain size of medical grade 304 and 316L stainless steel without altering their chemical composition (grain size range= 20μm-200nm) (4). Grain size control affected the nano-topography of the material surfaces which was measured by an Atomic Force Microscope (AFM). Grain sizes, such as 0.2, 0.5, 1, 2, 3, 9, and 10 μm, were used both polished and non-polished. All the stainless-steel samples were cleaned by treating with acetone and ethanol under sonication. Triplicates of all polished and non-polished samples with different grain sizes were subjected to magnetization of DM, 0.1T, 0.5T, and 1T, before seeding them with the bacteria. Controls were used in the form of untreated samples. Bacterial were grown in Tryptic Soy Broth (TSB). An actively growing bacterial suspension was seeded onto the stainless-steel discs into 24-well micro-titer plates and kept for incubation. After 24 hours of incubation, the stainless-steel discs were washed with Phosphate Buffer Saline (PBS) to remove the plankton bacteria and allow the sessile bacteria in the biofilm to remain. The degree of development of the bacterial biofilms on the stainless-steel discs were measured using spectrophotometric analysis. For this, the bacterial biofilm was removed from the stainless steel by sonication. The formation of biofilms was also determined by performing a biofilm staining method using Safranin. RESULTS SECTION: AFM results revealed a slight decrease in roughness by decreasing the grain size of the material. Moreover, the samples were segregated into two categories of polished and non-polished samples, in which polishing decreased roughness significantly. After careful analysis we found out that polished surfaces showed a higher degree for biofilm formation in comparison to the non-polished ones. We also observed that bacteria showed a higher rate for biofilm formation for the demagnetized samples, whereas 0.5T magnetization showed the least amount of biofilm formation. After 0.5T, there was no significant change in the rate of biofilm formation on the stainless-steel samples. Altogether, stainless steel samples containing 0.5 μm and less grainsize, and magnetized with 0.5 tesla and stronger magnets demonstrated the least degree of biofilm formation. DISCUSSION: In summary, the results demonstrate that controlling the grain size of medical grade stainless steel can control and mitigate bacterial responses on, and thus possibly infections of, orthopedic implants or other implantable devices. The research was funded by Komatsuseiki Kosakusho Co., Ltd (KSJ: Japan) SIGNIFICANCE/CLINICAL RELEVANCE: Orthopedic implants that more than 70% of them are made of metals (i.e., stainless steel, titanium, and cobalt-chromium alloys) are failing through loosening and breakage due to their limited mechanical properties. On the other hand, the risk of infection for these implants and its financial burden on our society is undeniable. We have seen that our uniformly nanograined stainless steel shows improved mechanical properties (i.e., higher stiffness, hardness, fatigue) as compared to conventional stainless steel along with the reduction of biofilm formation on its surface. These promising results made us to peruse the development of nanograined titanium and cobalt-chromium alloys for resolving the complications of orthopedic implants. 

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3. NanoSUS (Ultra Fine Grained Stainless-Steel) for Orthopedic Implants

   Bahram Saleh, Ada Vernet-Crua ( February 2021 , Orthopaedic Research Society)

   Statement of Purpose: Orthopedic implants are important therapeutic devices for the management of a wide range of orthopedic conditions. However, bacterial infections of orthopedic implants remain a major problem, and not an uncommon one, leading to an increased rate of osteomyelitis, sepsis, implant failure and dysfunction, etc. Treating these infections is more challenging as the causative organism protects itself by the production of a biofilm over the implant’s surface (1). Infections start by the adhesion and colonization of pathogenic bacteria such as Staphylococcus aureus (SA), Staphylococcus epidermidis (SE), Escherichia coli (E. coli), Methicillin-Resistant Staphylococcus aureus (MRSA), and Multi-Drug Resistant Escherichia coli (MDR E. coli) on the implant’s surfaces. Specifically, Staphylococcus comprises up to two-thirds of all pathogens involved in orthopedic implant infections (2). However, bacterial surface adhesion is a complex process influenced by several factors such as chemical composition, hydrophobicity, magnetization, surface charge, and surface roughness of the implant (3). Considering the intimate association between bacteria and the implant surface, we measured the effect of stainless-steel surface properties on bacterial surface attachment and subsequent formation of biofilms controlling above mentioned factors. Method: The prominent bacteria responsible for orthopedic implant infections (SA, SE, E. coli, MRSA, and MDR E. coli) were used in this study. We were able to control the grain size of medical grade 304 and 316L stainless steel without altering their chemical composition (grain size range= 20μm-200nm) (4). Grain size control affected the nano-topography of the material surfaces which was measured by an Atomic Force Microscope (AFM). Grain sizes, such as 0.2, 0.5, 1, 2, 3, 9, and 10 μm, were used both polished and non-polished. All the stainless-steel samples were cleaned by treating with acetone and ethanol under sonication. Triplicates of all polished and non-polished samples with different grain sizes were subjected to magnetization of DM, 0.1T, 0.5T, and 1T, before seeding them with the bacteria. Controls were used in the form of untreated samples. Bacterial were grown in Tryptic Soy Broth (TSB). An actively growing bacterial suspension was seeded onto the stainless-steel discs into 24-well micro-titer plates and kept for incubation. After 24 hours of incubation, the stainless-steel discs were washed with Phosphate Buffer Saline (PBS) to remove the plankton bacteria and allow the sessile bacteria in the biofilm to remain. The degree of development of the bacterial biofilms on the stainless-steel discs were measured using spectrophotometric analysis. For this, the bacterial biofilm was removed from the stainless steel by sonication. The formation of biofilms was also determined by performing a biofilm staining method using Safranin. Results: AFM results revealed a slight decrease in roughness by decreasing the grain size of the material. Moreover, the samples were segregated into two categories of polished and non-polished samples, in which polishing decreased roughness significantly. After careful analysis we found out that polished surfaces showed a higher degree for biofilm formation in comparison to the non-polished ones. We also observed that bacteria showed a higher rate for biofilm formation for the demagnetized samples, whereas 0.5T magnetization showed the least amount of biofilm formation. After 0.5T, there was no significant change in the rate of biofilm formation on the stainless-steel samples. Altogether, stainless steel samples containing 0.5 μm and less grainsize, and magnetized with 0.5 tesla and stronger magnets demonstrated the least degree of biofilm formation. Conclusion: In summary, the results demonstrate that controlling the grain size of medical grade stainless steel can control and mitigate bacterial responses on, and thus possibly infections of, orthopedic implants or other implantable devices. The research was funded by Komatsuseiki Kosakusho Co., Ltd (KSJ: Japan) 

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4. Electrophoretic deposition of MgO nanoparticles imparts antibacterial properties to poly‐L‐lactic acid for orthopedic applications

   https://doi.org/10.1002/jbm.a.36174  

   Hickey, Daniel J. ; Muthusamy, Divya ; Webster, Thomas J. ( August 2017 , Journal of Biomedical Materials Research Part A)

   Bacterial infection of implanted biomaterials is a serious problem that increases health care costs and negatively affects a considerable fraction of orthopedic procedures. In this field, magnesium oxide nanoparticles (MgO NPs) have emerged as a promising material to combat bacterial infection while maintaining or improving bone cell functions. Here, MgO NPs were electrophoretically deposited onto poly‐L‐lactic acid (PLLA) sheets to achieve a coating of highly exposed MgO NPs that directly influenced cell‐substrate interactions at short time scales. Samples were characterized for their surface chemistry, crystal structure, roughness, wettability, degradation characteristics, and their ability to support the growth of human fibroblasts and osteoblasts, as well as their resistance to colonization byStaphylococcus aureus,Staphylococcus epidermidis, andPseudomonas aeruginosa. In general, increasing the applied voltage during deposition increased the surface coverage of the coating and significantly decreased the colonization of all three bacterial strains (up to a 90% reduction). Furthermore,S. aureuscells that did attach onto substrates prepared at high voltages exhibited trademark signs of membrane damage and cell death. Importantly, MTS cell viability assays indicated that osteoblast adhesion increased with increasing deposition voltage, while fibroblast adhesion exhibited the opposite trend. Thus, although requiring more studies, this research provides the first evidence that MgO NP coatings prepared at relatively high voltages (120–150 V) may have the ability to resist bacterial colonization, promote bone cell attachment, and curb fibrous capsule formation. Therefore, it is recommended that this technology be further investigated and developed for numerous orthopedic applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3136–3147, 2017.

    

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5. Emerging role of metabolic signaling in synovial joint remodeling and osteoarthritis

   https://doi.org/10.1002/jor.23420  

   June, Ronald K. ; Liu‐Bryan, Ru ; Long, Fanxing ; Griffin, Timothy M. ( September 2016 , Journal of Orthopaedic Research)

   Obesity and associated metabolic diseases collectively referred to as the metabolic syndrome increase the risk of skeletal and synovial joint diseases, including osteoarthritis (OA). The relationship between obesity and musculoskeletal diseases is complex, involving biomechanical, dietary, genetic, inflammatory, and metabolic factors. Recent findings illustrate how changes in cellular metabolism and metabolic signaling pathways alter skeletal development, remodeling, and homeostasis, especially in response to biomechanical and inflammatory stressors. Consequently, a better understanding of the energy metabolism of diarthrodial joint cells and tissues, including bone, cartilage, and synovium, may lead to new strategies to treat or prevent synovial joint diseases such as OA. This rationale was the basis of a workshop presented at the 2016 Annual ORS Meeting in Orlando, FL on the emerging role of metabolic signaling in synovial joint remodeling and OA. The topics we covered included (i) the relationship between metabolic syndrome and OA in clinical and pre‐clinical studies; (ii) the effect of biomechanical loading on chondrocyte metabolism; (iii) the effect of Wnt signaling on osteoblast carbohydrate and amino acid metabolism with respect to bone anabolism; and (iv) the role of AMP‐activated protein kinase in chondrocyte energetic and biomechanical stress responses in the context of cartilage injury, aging, and OA. Although challenges exist for measuring in vivo changes in synovial joint tissue metabolism, the findings presented herein provide multiple lines of evidence to support a central role for disrupted cellular energy metabolism in the pathogenesis of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2048–2058, 2016.

    

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