Honors & News
May 21, 2016
Benoit Lab presents at World Biomaterials Congress
Several members of the Benoit Lab presented their research at the 10th World Biomaterials Congress (WBC) this weekend, held in Montreal. The largest gathering of Biomaterial Research, the WBC includes over 1,200 oral presentations and 2,400 poster presentations. Their respective presentation topics are below.
Enzymatically-responsive poly(ethylene glycol) hydrogels for the controlled delivery of
Introduction: Therapeutic angiogenesis holds great potential within regenerative medicine approaches, where insufficient vascularization limits construct size, complexity, and anastomosis with host vasculature. Many pro-angiogenic approaches have been developed, often via delivery of angiogenic proteins or peptides. Peptides typically mimic the bioactivity of larger proteins or growth factors, and offer advantages over traditional protein delivery. However, like proteins, peptides suffer from rapid clearance and poor pharmacokinetics when delivered systemically. Therefore, a poly(ethylene glycol) (PEG) hydrogel-based platform technology was developed to control and sustain peptide drug release via matrix metalloproteinase (MMP) activity.
Localized and Sustained Delivery of small interference RNA (siRNA) from Poly(Ethylene Glycol) (PEG) Hydrogels to Enhance Fracture Healing
Introduction: Impaired fracture healing, which commonly stems from reduced mesenchymal stem cell (MSC) osteogenic capacity, is a major clinical challenge-. To augment MSC function and subsequent fracture healing, known inhibitors of bone formation can be downregulated. For example, mouse knockouts of WW domain containing E3 ubiquitin protein ligase 1 (WWP1) exhibit robust fracture healing. To realize clinically-relevant approaches to enhance fracture healing motivated by gene knockout studies, siRNA delivery can be exploited. However, siRNA delivery has many challenges including inefficient delivery vehicles that are incapable of local and sustained delivery of protected siRNA to achieve tissue regeneration. Thus, we developed and tested a hybrid nanoparticle (NP)/hydrogel delivery system where NPs protect siRNA and increase siRNA delivery efficiency, while PEG hydrogels provide localized and sustained siRNA delivery by controlling release of embedded siRNA/NPs.
Nanoparticle-mediated delivery of siRNAs modulates mesenchymal stem cell differentiation
Introduction: Mesenchymal stem cells (MSC) are an attractive cell source for tissue engineering approaches due to multilineage differentiation. However, controlling MSC fate is critical for tissue regeneration. microRNAs (miRNA) are known as ‘master regulators' of differentiation, serving to integrate the myriad of complex signals driving differentiation . However, the use of small interfering RNA (siRNA), which are exogenous analogs of miRNA, to control MSC fate has been largely unexplored due to a paucity of delivery systems and poor appreciation for siRNAs necessary to achieve differentiation. Towards this end, we analyzed temporal expression of multiple miRNAs in MSCs undergoing osteogenesis in vitro. Subsequently, we used polymeric nanoparticles (NPs) previously shown to achieve successful siRNA delivery to MSCs  to deliver siRNA mimicking the identified miRNA while monitoring MSC differentiation.
Strategies to maintain acinar cell phenotype in vitro utilizing poly(ethylene glycol) hydrogels
Introduction: Over 500,000 people are diagnosed with head and neck cancers per year worldwide. Radiation therapy for these cancers causes extensive and permanent damage to secretory acinar cells within the salivary glands leading to permanent dry mouth for which no curative therapy exists. Cell-based therapies developed by the suspension culture of primary submandibular gland (SMG) cells has shown efficacy in restoring function after gland irradiation. However, regeneration is variable and the mechanism resulting in partial acinar regeneration in vivo is unclear,. To control acinar cell survival and function for subsequent transplantation in vivo, we are developing biomimetic poly(ethylene glycol) (PEG) hydrogels to culture primary SMG cells.
Peptide-functionalized polymers localize to remodeling osteoporotic bone
Introduction: Increased bone resorption by osteoclasts relative to bone formation by osteoblasts culminates in osteoporosis, a disease of low bone mass. There are myriad drugs in preclinical analyses that may enhance bone regeneration. However, these are largely small molecule drugs, which suffer from less than 1% bone accumulation. While bone targeting strategies exist, these approaches are general for bone matrix and not specific to where cellular remodeling is occurring, limiting targeted drug pharmacodynamics. We previously identified a peptide, TPLSYLKGLVTV, with high affinity to tartrate-resistant acid phosphatase (TRAP), a protein secreted by osteoclasts during the resorptive phase of bone remodeling. Targeting osteoanabolics to TRAP may enhance drug pharmacodynamics by increasing osteoblast activity specifically at sites of bone remodeling. This work developed TRAP-targeted polymer carriers as a platform for subsequent drug delivery approaches.
More information on these research projects can be found here.
May 16, 2016
Taithera, Inc. partners with UR Ventures to Commercialize Bone-Targeted Therapeutic Agent
Taithera, Inc., a New York City based biotech company, and UR Ventures, the technology commercialization office of the University of Rochester, today announced plans to commercialize a bone-targeted therapeutic agent. This precision medicine technology, invented at the University of Rochester's Center for Musculoskeletal Research, uses a peptide-based approach to deliver drugs directly to the bone for the diagnosis, treatment, and prevention of musculoskeletal diseases and disorders, including osteoporosis, bone cancer, bone fracture, bone allograft rejection, bone autograft rejection, and Paget's disease.
J. Edward Puzas, Ph.D., the Donald and Mary Clark Professor of Orthopaedics, and Danielle Benoit, Ph.D., Associate Professor of Biomedical Engineering and Chemical Engineering, co-led the development of this technology.
Taithera's co-founder and Chief Science Officer, Mo Chen, Ph.D. received his doctorate at the University of Rochester and conducted research at the Center for Musculoskeletal Research.
Rochester has been conducting extensive research on this bone-targeting therapeutic agent for more than six years, and animal models show that this bone-targeting technology has high affinity for tartrate-resistant acid phosphatase, an enzyme left by osteoclasts – the cells responsible for bone resorption. This means that drugs can be conjugates, or paired with, this targeting technology to deliver those drugs directly to the bone. This will significantly improve bone biodistribution.
Dr. Benoit said,
I have spent more than a decade developing polymeric delivery systems for biotherapeutics. For the past six years, my research has focused on developing novel targeting systems for bone-specific delivery of therapeutics. The results we have seen from this research show signs of something really quite revolutionary. I am thrilled that the University of Rochester and Taithera are working together to commercialize this technology. I look forward to working closely with Taithera.
Dr. Chen agrees.
There are few times in a scientist's career when you see a new technology that stands a strong chance to significantly improve millions of lives,he said.
The quality of the research and data at the University of Rochester is second to none. It is an honor to once again work with the Center for Musculoskeletal Research at the University of Rochester.
May 12, 2016
Collaborative project recommended for funding through CTSI Pilot Studies Program
A collaborative project involving Research Assistant Professor Ben Frisch and Associate Professor of Biomedical Engineering Danielle Benoit has been selected for funding. The proposal entitled,
Targeted delivery of cytotoxic agents for the eradication of leukemia stem cells in the bone marrowwas submitted for a pilot project grant through the Pilot Studies Program of the CTSI earlier this year. The program considered the application to be highly meritorious and deserving of a priority score.
May 10, 2016
Andrew Shubin successfully defends Ph.D. thesis!
Congratulations to Andrew Shubin for a successfully defending his Ph.D. Thesis! Andrew worked in the Benoit Lab, and his project, Poly(ethylene glycol) hydrogels for salivary gland regeneration, was supported by the National Institute for Dental and Craniofacial Research (R01 DE022949) and a Ruth Kirschstein National Research Service Award Fellowship through the National Cancer Institute (F30 CA183320).
May 10, 2016
Jomy Varghese successfully defends proposal
Congratulations to Jomy Varghese for a successful defense of his proposal! Joey is currently a graduate student in the Benoit Lab, and his current project is "Engineered Nanoparticles to Radioprotect Salivary Tissue (Supported by an NCI fellowship).
May 1, 2016
Graduate student Jomy Varghese awarded NCI Fellowship Grant
Jomy Varghese, a graduate student working in the Benoit Lab, was recently awarded an F30 Fellowship Grant from the National Cancer Institute (NCI). His project is titled
Engineered Nanoparticles to Radioprotect Salivary Tissueand deals with improving radiotherapy.
Project Description: Head and neck cancers comprise 6% of malignancies diagnoses annually, affecting 40,000 in the US and over 550,000 patients worldwide, who will then go on to receive radiotherapy. Radiation-induced xerostomia carries a significant risk for subsequent life threatening pathology and profoundly diminished quality of life by interfering with patients' ability to eat and sleep. We propose novel nanoparticle platforms for radioprotection via localized, controlled delivery of siRNA and antioxidant strategies, which have the potential to prevent xerostomia altogether for our patients, and to improve radiotherapy significantly.
April 28, 2016
Proposal by Frisch, Fasan and Benoit receives University Research Award
A collaborative project involving Research Assistant Professor Ben Frisch, Associate Professor of Chemisty Rudi Fasan, and Associate Professor of Biomedical Engineering Danielle Benoit has been chosen as one of the 2016-17 University Research Awards. One of just eight applications chosen by senior research leadership, the proposal entitled,
Targeted delivery of cytotoxic agents for the eradication of leukemia stem cells in the bone marrowwill be funded $72,600.
April 10, 2016
Benoit receives highly competitive score on NIH R01
Danielle Benoit and Hyun Koo of University of Pennsylvania recently received an outstanding score of 8 percent on an NIH Research Project Grant (R01.) The description of their project,
A novel anti-caries approach to modulate virulence of cariogenic biofilmsis below:
The development of novel chemotherapeutic approaches against cariogenic biofilms is challenging. Bacteria within biofilms are enmeshed in an exopolysaccharides (EPS)-rich matrix. Furthermore, EPS-embedded bacteria also create highly protected and acidic microenvironments that promote cariogenic biofilm build-up and acid-dissolution of tooth enamel. To overcome these remarkable challenges, our previous NIH supported (DE018023) studies developed a potent anti-caries approach by combining food-derived antibiofilm agents (myricetin and farnesol) with fluoride. We demonstrated that these agents in combination severely compromise EPS-matrix assembly and cariogenic biofilm development, resulting in a highly effective anti-caries therapy in vivo. Despite promising activity, there are limitations for further development and clinical translation of this approach. Both farnesol and myricetin are insoluble in aqueous solutions. In addition, retention of these agents at tooth-biofilm interface could be enhanced to maximize their efficacy in vivo. To address these hurdles, we have developed pH-responsive nanoparticle carriers (NPC) capable of co-encapsulating myricetin (Myr) and farnesol (Far) which were completely water-soluble, important towards practical formulations for human use. Furthermore, topically applied NPC bind avidly to pellicle and EPS, and accumulate within biofilms. Excitingly, NPC respond to acidic pH to release agents more rapidly at acidic (pathological) versus neutral (physiological) pH, greatly improving (~20-fold more effective than free agents) antibiofilm activity in vitro. We hypothesize that NPC will substantially amplify the efficacy of our combination therapy (CT) via increased solubility, retention and pH-activated release of active agents with fluoride. To support our hypothesis, Aim 1 will optimize physicochemical properties of NPC to improve targeted delivery of our agents, and thereby potentiate their antibiofilm efficacy. We will focus on increasing the kinetics of NPC pH-responsive drug release to ensure maximal release of the agents at pH consistent with the acidic biofilm milieu. Then, Aim 2 will evaluate the efficacy of optimized NPCs containing Myr and Far with fluoride (CT-NPC) using our in vitro cariogenic biofilm model. We have previously identified the major biological actions (EPS synthesis and acidogenicity) and molecular targets (gtfB, atpD) of our therapy. Thus, we will investigate how CT-NPC disrupts these virulence properties more effectively than CT using novel methods to assess spatiotemporal development of EPS matrix, acidic pH niches and gene expression in situ within intact 3D biofilms. Aim 3 will evaluate the efficacy of the developed CT-NPC in disrupting cariogenic biofilms and reducing dental caries in vivo using a rodent model of dental caries under clinically-relevant topical treatment regimen. CT-NPC will be also compared to ‘gold standards' of caries prevention (fluoride) and antimicrobial therapy (chlorhexidine). Successful completion of these aims will lead to a highly efficacious and clinically-translatable therapy that may be superior to current anti-plaque/anti-caries modalities and will motivate formulation development for clinical studies.
April 8, 2016
Last year, BME Professor Danielle Benoit received a Faculty Early Career Development (CAREER) award, the most prestigious grants given by the National Science Foundation to junior faculty members. This article details her research and presents her tips for junior faculty members interested in applying for a CAREER award.
"The challenge with drug delivery to bone tissue is that there's currently no good way to target the drugs exactly where they are needed," says Danielle Benoit, the James P. Wilmot Distinguished Associate Professor of Biomedical Engineering. Her goal: Develop a drug delivery system that can be targeted to specific parts of the skeleton to treat osteoporosis.
- Local and targeted drug delivery for bone regeneration.Curr Opin Biotechnol. 40, 125-132. (2016 Apr 08).
- Targeted, triggered drug delivery to tumor and biofilm microenvironments.Nanomedicine (Lond). 11, 873-9. (2016 Apr 01).
- Enzymatically-responsive pro-angiogenic peptide-releasing poly(ethylene glycol) hydrogels promote vascularization in vivo.J Control Release. 217, 191-201. (2015 Nov 10).