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Bacteria Responsible for Incurable Bone Infection Hide in Bone Micro-Channels

Tuesday, December 27, 2016

Bacteria that cause life-threatening and incurable bone infections may elude immune or antibiotic attack by hiding in tiny channels within bone, according to researchers at the University of Rochester Medical Center (URMC). Researchers in the Center for Musculoskeletal Research (CMSR) conducted the first systematic study to define where and how Staphylococcus aureus hides in bones, yielding the first demonstration that the bacteria can change shape and “move” to colonize tiny channels in mouse bone.

S. aureus is a common bacteria that can cause painful skin infections or life-threatening blood or bone infections. Because it can form bacterial communities deep within bone where it can survive for long periods of time, S. aureus bone infections are extremely difficult and costly to treat. Patients with S. aureus bone infections are often treated with antibiotics and undergo surgery to remove infected tissue, but infection recurs in 40 percent of patients and amputation of infected limbs is sometimes necessary.

“The challenge with bone infections is that they tend to be incurable,” said Edward Schwarz, Ph.D., Richard and Margaret Burton Distinguished Professor in Orthopaedics and director of the CMSR. “Surgeons take extra margins around infected bone, reconstruct, and the infection comes back. They don't understand why this infection keeps coming back and neither did we.”

To investigate, lead author, Karen de Mesy Bentley, M.S., director of the Electron Microscopy Shared Laboratory and faculty associate in the Department of Pathology and Laboratory Medicine at URMC, performed systematic transmission electron microscopy (TEM) of S. aureus infected mouse femurs and tibias. Mice were infected with S. aureus directly or via contaminated implants 14 days prior to imaging.

Read More: Bacteria Responsible for Incurable Bone Infection Hide in Bone Micro-Channels

Pushing the Boundaries of Musculoskeletal Research

Wednesday, December 21, 2016

Researchers in URMC’s Center for Musculoskeletal Research (CMSR) are on the cusp of translating some important research into clinical use. Specifically, teams in the Center have developed a vaccine that they hope will prevent one of the most challenging and deadly infections, methicillin-resistant Staphylococcus aureus (MRSA), and are combining 3D printing with stem cell technologies to produce personalized bone replacements. 

Working Toward a MRSA Vaccine

MRSA is sometimes referred to as a “superbug” due to its ability to survive most antibiotic treatments that easily thwart other bacteria. During standard orthopaedic surgeries, a small percentage of patients acquire life-threatening MRSA infections that can be extremely difficult and costly to treat. Patients may spend years battling re-infections and undergoing multiple surgeries to remove infected tissue and keep the superbug at bay.

A MRSA vaccine would help patients avoid that suffering, and Edward Schwarz, Ph.D., director of the CMSR and Richard and Margaret Burton Distinguished Professor in Orthopaedics, believes he is closer than anyone else to producing that vaccine. In fact, he has produced a monoclonal antibody vaccine that he hopes will be in clinical trials by 2018.

Read More: Pushing the Boundaries of Musculoskeletal Research

Bentley Hunt and David Abplanap receive 2016 CMSR Symposium Distinguished Abstract Awards

Monday, September 26, 2016

Two Awad Lab graduate students, Bentley Hunt and David Abplanap, were selected to receive a CMSR Symposium Distinguished Abstract Award this year. This new award recognizes outstanding abstracts that were submitted for the 2016 poster session. Below are the winning abstracts for both students.

Bentley Hunt

Bentley Hunt

Critical-sized bone defects are the result of tumor resection or severe injury and require surgical intervention to regenerate the bone and salvage the limb. The current “gold standard” to treat critical-sized defects is cadaveric allografts; however, these grafts have a 25% failure rate due to fibrotic non-unions and post-surgery fractures and if successful, the grafts only have a 5-10 year lifespan. These limitations have been attributed to the absence of an osteoinductive component and slow remodeling of the graft in vivo. The optimal standard of healing is an autograft due to the presence of the periosteum. This cortical bone lining tissue contains a depot of stem cells, osteoprogenitors, and a vascular network that act as the origin of angiogenesis and osteogenesis after fracture. It has been shown that live autografts without a periosteum result in a 10-fold decrease in neovascularization and 73% reduction in new bone formation compared to a complete autograft. Therefore, we hypothesize the delivery of a vascularized periosteum biomimetic will improve the regeneration of critical-sized bone defects. We have previously demonstrated the feasibility of delivering mesenchymal stem cell (MSC) sheets to treat a critical-sized mouse femoral defect, which enhanced osteogenesis of a devitalized allograft during repair. The objective of this study was to determine the feasibility and culture conditions for in vitro vascularization of a MSC sheet. We hypothesize that co-culturing MSCs and endothelial cells (ECs) in vitro can produce a premature vessel network within the MSC sheet to act as an origin of angiogenesis when implanted in vivo. MSCs and ECs were co-cultured for 5 days or 4 weeks while varying the percent O2 [5% & 21%], the percent ECs in co-culture [25%- 40%], and the seeding strategy [mixed, concurrent and lamellar]. After 5 days in culture, network formation could be seen in cultures under 21% O2, but there was limited network formation at 5% O2 while EC culture alone was not affected. After 4 weeks in culture, varying the percent endothelial cells from 25% to 40% did not significantly change the quantified capillary density, which was ~100 cm-1. A concurrent, mixed seeding strategy resulted in an increased capillary density and more branched morphology of the formed network as compared to a lamellar seeding strategy. Texas Red dextran staining surrounded by GFP+ expression indicated lumen formation in the co-culture system with lumen diameters ranging from 6 to 13 microns. Mouse derived co-cultures (mACD31+/C3H) produced a significantly increased capillary density compared to human derived co-cultures (HUVEC/hMSC) and surpassed the capillary densities seen in the periosteum of mouse tibia and calvarium. These data indicate that 21% O2, >25% ECs in co-culture, and a mixed seeding strategy produced optimized human and mouse vascularized cell sheets with branching, interconnected structures. These structures also show evidence of lumen formation in vitro. The vascularized mouse cell sheets also produce a capillary density surpassing that seen in the tibia and calvarium. All these factors support feasibility for pre-vascularizing a MSC sheet and its delivery for an early revascularization of critical sized defects. Moving forward, we plan to graft these vascularized cell sheets onto our 3D printed calcium phosphate scaffolds, which will be tested in vivo using an established mouse critical sized calvarial defect model. The current gold standard treatment for large bone defects is devitalized allografts, but allografts have a limited lifespan and often require multiple reconstructive surgeries. Delivery of pre-vascularized stem cell sheets could improve large defect regeneration through early revascularization and osteogenic induction, and ultimately provide a long-lasting surgical option.

David Abplanap

David Abplanap

Flexor tendon injuries are some of the most difficult insults to the hands for doctors to treat and restore to natural function. Following reparative surgery, the healing process is fraught with formation of debilitating tendon adhesions as well as increased likelihood of tendon rupture requiring another surgical intervention. Our lab studies the unique biology behind the healing process of the flexor tendon searching for ways in which we can manipulate this biology to achieve a more regenerative healing process. The MRL/MpJ (MRL) mouse strain has been widely studied as a potential mammalian model of regenerative-like healing and has shown promising results in an Achilles tendon defect model but the specific process allowing for this improved healing capacity is still unknown. Additionally, the degree of regenerative healing observed in these mice varies significantly between tissue types as well as methods of injury. We hypothesize that the MRL strain will demonstrate an improved healing response in our flexor tendon injury model, forming smaller adhesions and recovering more native tendon strength. Additionally, we propose that this improved functional outcome is a result of the different immunological response to injury in this strain compared to C57/Bl6 (C57). Age-matched (10 weeks) MRL and C57 mice were subjected to a bi-lateral partial laceration of the deep digital flexor tendon in the middle digit of the hind paws. Hind limbs were harvested for mechanical testing and histology at 2, 4, and 8 weeks following injury (along with Day 0 uninjured controls). Blood serum was extracted at Days 1, 3, 5, 7, and 14 following injury and subjected to inflammatory cytokine/chemokine, MMP, and TGF-β serum analysis panels respectively (along with Day 0 uninjured controls). In examining histology, we can clearly see an enhanced cellular response to injury (higher observed cell density and number) both in the injured tendon as well as surrounding tissue in C57 compared to a more localized response (seemingly tendon tissue specific) in MRL at 2-weeks. This enhanced level of cellularity in C57 is maintained through the 4-week timepoint and remains elevated at the 8-week end point in C57 whereas MRL shows significant reductions in hypercellularity by 4 weeks. At the end of the 8-week time course, MRL appears to exhibit less adhered tissue between tendon and the synovial sheath as well as more complete resolution of the initial insult to the tendon when compared to C57. Examining the blood serum, it appears that the C57 response to injury is more aggressive exhibiting higher up-regulation of hallmark inflammatory cytokines (IL-1, IL-6, IL-17, TNF-α) in both early (D1/D3) and late stages (D14) of the healing response compared to MRL. These results lead us to conclude that the MRL mouse does indeed exhibit a different healing response to flexor tendon injury than C57 and that this response results in an improved biomechanical outcome after injury. It also appears that the specific immune response to injury could in some way be contributing to this improved outcome and that the blunted inflammatory response observed in MRL could target a less fibrotic more regenerative healing pathway when compared to C57. These results motivate further study of the MRL mouse in this injury model to better understand their unique healing pathway while highlighting the inflammatory response as a potential source of the observed differences in healing response and overall quality of repair.

6th Annual CMSR Symposium

Wednesday, September 14, 2016

Wednesday, September 28, 2016 • Flaum Atrium and Class of ’62 Auditorium

Read More: 6th Annual CMSR Symposium

Immune Cell’s Role in Rheumatoid Arthritis-Induced Bone Loss Revealed

Tuesday, August 23, 2016

Investigators supported in part by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have uncovered a mechanism by which B cells, the antibody-producing cells of the immune system, contribute to bone degradation in rheumatoid arthritis (RA). The study showed that B cells produce a molecule called RANKL, which stimulates the generation of bone-destroying cells called osteoclasts. The findings, which were reported in Arthritis and Rheumatology, suggest that targeting B cells and the RANKL pathway could be an effective strategy for preserving bone in people with the disease.

Read More: Immune Cell’s Role in Rheumatoid Arthritis-Induced Bone Loss Revealed

$19M Grant Will Help URMC Speed Medical Advances to Patients

Thursday, August 11, 2016

The University of Rochester Medical Center has been awarded more than $19 million from the National Institutes of Health (NIH) to continue programs that remove hurdles in the process of applying medical research to patient treatment and population health. The award will support “bench-to-bedside” research and is the Medical Center’s third consecutive translational science award, bringing total funding from these grants to almost $86 million.

The University of Rochester Clinical and Translational Science Institute (UR CTSI) was one of the first 12 institutions in the nation to receive a Clinical and Translational Science Award (CTSA), a program which was established by the NIH’s Center for Advancing Translational Science in 2006 to help get new therapies to patients faster and to improve the health of the general population. In addition to the new funding, the UR CTSI has provided research support to investigators across the University that aided them in collectively obtaining nearly $58 million of further NIH funding over the past decade.

“Ten years ago the University of Rochester was catapulted to the forefront of the National Institutes of Health’s initiative to reengineer our nation’s biomedical research enterprise,” said Joel Seligman, president and CEO of the University of Rochester. “This award marks another important milestone in our efforts to bring together the scientific talent, the resources, and the expertise necessary to advance medicine and improve health.” 

Read More: $19M Grant Will Help URMC Speed Medical Advances to Patients

Home Team Advantage

Wednesday, August 3, 2016

Kenneth DeHaven was “a one-man band,” he says, when he started Rochester’s sports medicine program under new orthopaedics chair C. McCollister (Mac) Evarts ’57M (MD), ’64M (Res) in 1975. By embracing and working to perfect promising experimental techniques, DeHaven put the program on the path to becoming a regional destination for athletes.

Read More: Home Team Advantage

URMC Researchers Look for Better Treatments, Cures for Juvenile Arthritis

Monday, July 25, 2016

Most people are familiar with arthritis as a disease of middle or late life. We associate the term with stiff, swollen joints in the fingers, knees, and hips of a graying population. However, arthritis also occurs in children and infants.

According to the Centers for Disease Control, there are about 300,000 children living with some form rheumatic disease in the US alone. The Arthritis National Research Foundation has designated July “Juvenile Arthritis Awareness Month” to help spread the word about this constellation of diseases and the importance of conducting research to better understand them.

Homaira Rahimi, M.D., M.S., assistant professor of Pediatrics and pediatric rheumatologist at the University of Rochester Medical Center, studies juvenile idiopathic arthritis (JIA). JIA is the most prevalent form of chronic arthritis and currently affects somewhere between 70,000 – 100,000 children in the US. There are seven subsets of JIA, which involve combinations of the following: swelling and pain in one or more joints, rash, fevers, inflammation of other organs – especially the eyes, and periods of remission and flare.

Read More: URMC Researchers Look for Better Treatments, Cures for Juvenile Arthritis

Center for Musculoskeletal Research Renews $4 Million Grant from NIH and Launches the Brodell Musculoskeletal Research Fund

Wednesday, June 29, 2016

The Center for Musculoskeletal Research at the University of Rochester Medical Center recently received renewal of a five year, $4 million grant from the National Institutes of Health. The large “P30 Core Center” grant will allow the CMSR to continue to provide infrastructure and career development support to musculoskeletal researchers across the university.

CMSR faculty at their 2015 symposium

Under the direction of Edward Schwarz, Ph.D., the Richard and Margaret Burton Distinguished Professor in Orthopaedics, the CMSR has consistently ranked as one of the top NIH-funded orthopaedic research programs in the country. Schwarz attributes this success largely to the quality of the faculty in the CMSR and the center’s focus on promoting the next generation of scientists and national leaders.  Most notable among these leaders in the P30 renewal are three new Directors: Laura Calvi, M.D. associate director of the Administration Core, Jennifer Jonason, Ph.D. co-director of the Histology, Biochemistry, and Molecular Imaging Core, and Danielle Benoit, Ph.D. co-director of the Biomechanics Biomaterials and Multimodal Tissue Imaging Core.

“Our center focuses on developing the most valuable resource in Musculoskeletal Research: its research talent,” says Schwarz.

Over the past five years, the previous P30 grant helped the CMSR support and advance faculty to independence. With robust efforts to support new investigators – via small pilot grants and a highly successful mentorship program funded by the P30 – the CMSR has grown from two tenure-track assistant professors to 16. Pilot grant funding allowed many non-tenure track and clinical faculty to obtain preliminary data that was critical for gaining subsequent independent funding and led to many academic promotions.

James David Brodell, Sr. ’83M (Res) and Ann Pearsall

In the current round of funding, the CMSR plans to expand the Pilot Grant Program using institutional and philanthropic funding. In fact, James David Brodell, Sr. ’83M (Res) and Ann Pearsall Brodell established a new pilot fund to provide seed money for fledgling projects in orthopaedic medicine and surgery in the fall of 2015.

The inaugural Harold Louis Brodell, M.D. ’54 and Alma Jean Brodell Musculoskeletal Research Fund, named in honor of Brodell’s parents, will supplement the 2016 P30 Pilot Grant awarded to John C. Elfar, M.D., who studies innovative ways to treat peripheral nerve injuries. The work could provide wide-ranging benefits to civilians and military personnel with limb injuries.

Four other $20,000 P30 pilot grants were awarded to:

  • Yahui Grace Chiu, Ph.D., “Functional and Phenotypical Characterization of a Novel Subset of DC-STAMP+ T cells”
  • Jennifer Jonason, Ph.D., “The Role of RUNX2 in the Progression of Post-Traumatic Osteoarthritis”
  • Catherine Kuo, Ph.D., “Axial and Limb Tendon Progenitor Cell Baseline and FGF4-Induced Differences”
  • Hengwei Zhang, Ph.D., “Proteasome inhibition enhanced bone fracture healing through PDGFR signaling”

The P30 grant renewal will also fund several core resources provided by the CMSR some of which are under new direction

  • Histology, Biochemistry, and Molecular Imaging (HBMI) Core offers guidance and support for histological processing, staining, imaging, analysis, and protocol optimization.  In addition, the core aids in development of primary cellular culture models and biochemical assays.
  • Biomechanics Biomaterials and Multimodal Tissue Imaging (BBMTI) Core provides subsidized, cost-effective access and training for new investigators in the biomechanical assessment of biomaterials and musculoskeletal tissues. This includes longitudinal imaging using micro-CT, fluorescent, bioluminescent, and ultrasound technology.
  • Kenneth DeHaven Arthroscopic Surgical Skills Laboratory (KDASSL) offers critically important laboratory training in human cadaver skills and provides opportunities for use of donated human tissue in research.

The CMSR offers facilities, services, and opportunities for collaboration among researchers across the university to help streamline and accelerate basic, translational, and clinical musculoskeletal research.  

Read More: Center for Musculoskeletal Research Renews $4 Million Grant from NIH and Launches the Brodell Musculoskeletal Research Fund

Antioxidants May Help Total Joint Replacements Last Longer

Tuesday, May 24, 2016

Infusing antioxidants into the plastic surface between metal components of total joint replacements may help the implants last longer and reduce damage to surrounding bone. A group of researchers in the Center for Musculoskeletal Research at the University of Rochester Medical Center showed that an antioxidant, called COVERNOX™, promotes both destruction and rebuilding of bone in a mouse model, but favors rebuilding.

About 7 million people are currently living with a hip or knee replacement in the US, which is a common last resort for end-stage joint disease. Many adults with severe osteoarthritis in their 50’s or 60’s are undergoing total joint replacement surgery, meaning that implants may need to last 30 or 40 years. However, twenty percent of patients experience implant failure within 10 years of their original surgery.

“Joint replacement surgery is largely regarded as the most successful medical procedure of the 20th century, but implants are not permanent,” says Edward Schwarz, PhD, director and Richard and Margaret Burton Distinguished Professor of Orthopaedics in the Center for Musculoskeletal Research at the University of Rochester Medical Center. “They wear out like tires on a car.”

Read More: Antioxidants May Help Total Joint Replacements Last Longer

Award Honors Staff who Exemplify Meliora

Friday, April 22, 2016

he Meliora Award recognizes staff members whose work performance and dedication during the preceding year exemplify the University’s motto, Meliora (“Ever Better”).

President and CEO Joel Seligman and Robert Witmer Jr., chairman emeritus of the Board of Trustees, will present the Meliora Awards—as well the Witmer Award for Distinguished Service and Staff Community Service Award—at a reception in honor of the recipients on Wednesday, April 27.

Read More: Award Honors Staff who Exemplify Meliora

Award Honors Staff who Exemplify Meliora

Friday, April 22, 2016

The Meliora Award recognizes staff members whose work performance and dedication during the preceding year exemplify the University’s motto, Meliora (“Ever Better”).

President and CEO Joel Seligman and Robert Witmer Jr., chairman emeritus of the Board of Trustees, will present the Meliora Awards—as well the Witmer Award for Distinguished Service and Staff Community Service Award—at a reception in honor of the recipients on Wednesday, April 27.

Read More: Award Honors Staff who Exemplify Meliora

AIR Researchers Demonstrate Role for B Cells in Bone Erosion in RA

Thursday, April 14, 2016

AIR researchers have uncovered a new mechanism of bone erosion and a possible biomarker for rheumatoid arthritis (RA). The group is the first to demonstrate that immune cells, called B cells, contribute directly to the breakdown of bone in RA by producing a signaling molecule called RANKL.

Read More: AIR Researchers Demonstrate Role for B Cells in Bone Erosion in RA

2015 Incubator Awardee: Michael Zuscik, MS, PhD

Tuesday, March 29, 2016

Dr. Michael Zuscik, Associate Professor of Orthopaedics, and Director of Educational Programs at the Center for Musculoskeletal Research, will serve as the Principal Investigator for the 2015 CTSI Incubator project.  The central focus of Dr. Zuscik’s research can be divided programmatically into two parts: 1) the study of the contribution of chondrogenesis and chondrocyte differentiation to the process of fracture repair and 2) the study of the behavior of the articular chondrocyte under normal conditions in healthy joints and during pathologic situations such as joint degeneration. The complex interplay between several key signaling mechanisms, including the TGF-beta, Wnt/beta-catenin and PTH/PTHrP pathways, are important for modulating chondrocyte differentiation and physiology and thus have a critical contribution to play during the fracture healing and joint maintenance/disease.

Read More: 2015 Incubator Awardee: Michael Zuscik, MS, PhD

2015 Incubator Awardee: Michael Zuscik, MS, PhD

Tuesday, March 29, 2016

Dr. Michael Zuscik, Associate Professor of Orthopaedics, and Director of Educational Programs at the Center for Musculoskeletal Research, will serve as the Principal Investigator for the 2015 CTSI Incubator project.  The central focus of Dr. Zuscik’s research can be divided programmatically into two parts: 1) the study of the contribution of chondrogenesis and chondrocyte differentiation to the process of fracture repair and 2) the study of the behavior of the articular chondrocyte under normal conditions in healthy joints and during pathologic situations such as joint degeneration. The complex interplay between several key signaling mechanisms, including the TGF-beta, Wnt/beta-catenin and PTH/PTHrP pathways, are important for modulating chondrocyte differentiation and physiology and thus have a critical contribution to play during the fracture healing and joint maintenance/disease.

Read More: 2015 Incubator Awardee: Michael Zuscik, MS, PhD

New Award Will Advance Muscular Dystrophy Research

Tuesday, March 8, 2016

Dr. Thornton

University of Rochester Medical Center (URMC) neurologist Charles Thornton, M.D. has received a Javits Neuroscience Investigator Award from the National Institutes of Health to further his research on muscular dystrophy. The unique award provides exceptional researchers with seven years of uninterrupted funding.

The Javits Neuroscience Investigator Award was created by the U.S. Congress in 1983 and is named in honor of former U.S. Senator Jacob Javits (NY), who was the victim of amyotrophic lateral sclerosis, a degenerative neurological disorder commonly known as Lou Gehrig’s disease. The $2.3 million grant is administered by the National Institute of Neurological Disorders and Stroke and is given to scientists who have demonstrated exceptional scientific excellence and productivity in their field.

Making progress on treating paralytic diseases is difficult and requires a dedicated team of clinicians and researchers, said Thornton, the Saunders Family Distinguished Professor in Neuromuscular Research. To bring a team together and keep it together over the long run, you need a stable stream of financial support. This award will help us continue our work through a very important stage when new therapies are being tested and others are on the horizon.

Read More: New Award Will Advance Muscular Dystrophy Research

2015-16 Faculty Pilot Program Awardee: Emily Carmody, MD

Thursday, February 18, 2016

Emily Carmody, MD, Assistant Professor of Orthopaedics and Assistant Professor at the Wilmot Cancer Center will lead a team of investigators through an exciting pilot project over the next year. Dr. Carmody specializes in treating both benign and malignant musculoskeletal tumors in adults and children. She has a particular interest in limb-sparing surgery and endoprosthetic reconstruction for treating bone sarcomas. Dr. Carmody also specializes in metabolic bone disorders including osteoporosis and osteopenia.

Dr. Carmody, along with Michael Zuscik, PhD (Associate Professor of Orthopaedics) and Christopher Ritchlin (Professor of Medicine) on a pilot project entitled “Assessment of Forteo as a Therapeutic to Treat Knee Osteoarthritis.” Traditional treatment strategies for Osteoarthritis are palliative, with the focus on pain management and joint replacement. Development of disease-modifying agents that can rejuvenate cartilage is a great unmet need. Thus, development of an effective treatment for Osteoarthritis is a vital public health initiative with potential for tremendous impact.

Read More: 2015-16 Faculty Pilot Program Awardee: Emily Carmody, MD