Browsing by Author "Young, Simon"

Now showing 1 - 9 of 9
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    Evaluation of Bone Regeneration Using the Rat Critical Size Calvarial Defect
    (Nature Publishing Group, 2012-10) Spicer, Patrick P.; Kretlow, James D.; Young, Simon; Jansen, John A.; Kasper, F. Kurtis; Mikos, Antonios G.
    Animal models that are reliably reproducible, appropriate analogues to the clinical condition they are used to investigate, and that offer minimal morbidity and periprocedural mortality to the subject are the keystone to the preclinical development of translational technologies. For bone tissue engineering, a number of small animal models exist. Here we describe the protocol for one such model, the rat calvarial defect. This versatile model allows for evaluation of biomaterials and bone tissue engineering approaches within a reproducible, nonload-bearing orthotopic site. Critical steps to ensure appropriate experimental control and troubleshooting tips learned through extensive experience with this model are provided. The surgical procedure itself takes approximately 30 minutes to complete with approximately 2 hours of perioperative care, and tissue harvest is generally performed 4 to 12 weeks postoperatively. Several analytical techniques are presented, which evaluate the cellular and extracellular matrix components, functionality and mineralization, including histological, mechanical and radiographic methods.
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    Hydrogel delivery of sting immunotherapy for treatment cancer
    (2024-04-30) Young, Simon; Leach, David; Hartgerink, Jeffrey D.; Rice University; The Board of Regents of the University of Texas System; United States Patent and Trademark Office
    In one aspect, the present disclosure provides for novel compositions of matter comprising multi domain peptide (MDP) hydrogels and cyclic dinucleotides (CDNs). Also disclosed are method of using such compositions in the treatment of cancer, including in particular the treatment of head and neck cancers, such as those resistant to CDN therapy.
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    Local Anti–PD-1 Delivery Prevents Progression of Premalignant Lesions in a 4NQO-Oral Carcinogenesis Mouse Model
    (American Association for Cancer Research, 2021) Shi, Yewen; Xie, Tong-xin; Leach, David G.; Wang, Bingbing; Young, Simon; Osman, Abdullah A.; Sikora, Andrew G.; Ren, Xiaoyong; Hartgerink, Jeffrey D.; Myers, Jeffrey N.; Rangel, Roberto
    Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti–PD-1 antibodies to prevent malignant progression of OPLs. Prevention Relevance: Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.
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    Revolutionizing bone regeneration: advanced biomaterials for healing compromised bone defects
    (Frontiers Media S.A., 2023) Awad, Kamal; Ahuja, Neelam; Yacoub, Ahmed S.; Brotto, Leticia; Young, Simon; Mikos, Antonios; Aswath, Pranesh; Varanasi, Venu
    In this review, we explore the application of novel biomaterial-based therapies specifically targeted towards craniofacial bone defects. The repair and regeneration of critical sized bone defects in the craniofacial region requires the use of bioactive materials to stabilize and expedite the healing process. However, the existing clinical approaches face challenges in effectively treating complex craniofacial bone defects, including issues such as oxidative stress, inflammation, and soft tissue loss. Given that a significant portion of individuals affected by traumatic bone defects in the craniofacial area belong to the aging population, there is an urgent need for innovative biomaterials to address the declining rate of new bone formation associated with age-related changes in the skeletal system. This article emphasizes the importance of semiconductor industry-derived materials as a potential solution to combat oxidative stress and address the challenges associated with aging bone. Furthermore, we discuss various material and autologous treatment approaches, as well as in vitro and in vivo models used to investigate new therapeutic strategies in the context of craniofacial bone repair. By focusing on these aspects, we aim to shed light on the potential of advanced biomaterials to overcome the limitations of current treatments and pave the way for more effective and efficient therapeutic interventions for craniofacial bone defects.
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    Self-assembling peptides as immunomodulatory biomaterials
    (Frontiers Media S.A., 2023) Hernandez, Andrea; Hartgerink, Jeffrey D.; Young, Simon
    Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides’ characteristics and current applications in immunomodulatory therapeutics.
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    SiONx Coating Regulates Mesenchymal Stem Cell Antioxidant Capacity via Nuclear Erythroid Factor 2 Activity under Toxic Oxidative Stress Conditions
    (MDPI, 2024) Ahuja, Neelam; Awad, Kamal; Yang, Su; Dong, He; Mikos, Antonios; Aswath, Pranesh; Young, Simon; Brotto, Marco; Varanasi, Venu; Center for Engineering Complex Tissues; Center for Excellence in Tissue Engineering
    Healing in compromised and complicated bone defects is often prolonged and delayed due to the lack of bioactivity of the fixation device, secondary infections, and associated oxidative stress. Here, we propose amorphous silicon oxynitride (SiONx) as a coating for the fixation devices to improve both bioactivity and bacteriostatic activity and reduce oxidative stress. We aimed to study the effect of increasing the N/O ratio in the SiONx to fine-tune the cellular activity and the antioxidant effect via the NRF2 pathway under oxidative stress conditions. The in vitro studies involved using human mesenchymal stem cells (MSCs) to examine the effect of SiONx coatings on osteogenesis with and without toxic oxidative stress. Additionally, bacterial growth on SiONx surfaces was studied using methicillin-resistant Staphylococcus aureus (MRSA) colonies. NRF2 siRNA transfection was performed on the hMSCs (NRF2-KD) to study the antioxidant response to silicon ions. The SiONx implant surfaces showed a >4-fold decrease in bacterial growth vs. bare titanium as a control. Increasing the N/O ratio in the SiONx implants increased the alkaline phosphatase activity >1.5 times, and the other osteogenic markers (osteocalcin, RUNX2, and Osterix) were increased >2-fold under normal conditions. Increasing the N/O ratio in SiONx enhanced the protective effects and improved cell viability against toxic oxidative stress conditions. There was a significant increase in osteocalcin activity compared to the uncoated group, along with increased antioxidant activity under oxidative stress conditions. In NRF2-KD cells, there was a stunted effect on the upregulation of antioxidant markers by silicon ions, indicating a role for NRF2. In conclusion, the SiONx coatings studied here displayed bacteriostatic properties. These materials promoted osteogenic markers under toxic oxidative stress conditions while also enhancing antioxidant NRF2 activity. These results indicate the potential of SiONx coatings to induce in vivo bone regeneration in a challenging oxidative stress environment.
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    Stimulator of Interferon Genes Pathway Activation through the Controlled Release of STINGel Mediates Analgesia and Anti-Cancer Effects in Oral Squamous Cell Carcinoma
    (MDPI, 2024) Dong, Minh Phuong; Dharmaraj, Neeraja; Kaminagakura, Estela; Xue, Jianfei; Leach, David G.; Hartgerink, Jeffrey D.; Zhang, Michael; Hanks, Hana-Joy; Ye, Yi; Aouizerat, Bradley E.; Vining, Kyle; Thomas, Carissa M.; Dovat, Sinisa; Young, Simon; Viet, Chi T.
    Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact.
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    STINGel: Controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy
    (Elsevier, 2018) Leach, David G.; Dharmaraj, Neeraja; Piotrowski, Stacey L.; Lopez-Silva, Tania L.; Lei, Yu L.; Sikora, Andrew G.; Young, Simon; Hartgerink, Jeffrey D.
    Recent advancements in the field of immunotherapy have yielded encouraging results for the treatment of advanced cancers. Cyclic dinucleotides (CDNs) are a powerful new class of immunotherapy drugs known as STING (Stimulator of Interferon Genes) agonists, currently in clinical trials. However, previous studies of CDNs in murine cancer models have required multiple injections, and improve survival only in relatively nonaggressive tumor models. Therefore, we sought to improve the efficacy of CDN immunotherapy by developing a novel biomaterial we call “STINGel.” STINGel is an injectable peptide hydrogel that localizes and provides controlled release of CDN delivery, showing an 8-fold slower release rate compared to a standard collagen hydrogel. The carrier hydrogel is a positively charged, MultiDomain Peptide (MDP) which self-assembles to form a nanofibrous matrix and is easily delivered by syringe. The highly localized delivery of CDN from this nanostructured biomaterial affects the local histological response in a subcutaneous model, and dramatically improves overall survival in a challenging murine model of head and neck cancer compared to CDN alone or CDN delivered from a collagen hydrogel. This study demonstrates the feasibility of biomaterial-based immunotherapy platforms like STINGel as strategies for increasing the efficacy of CDN immunotherapies.
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    The effect of simultaneous, controlled release of angiogenic and osteogenic growth factors on the enhancement of osteogenesis within craniofacial defects
    (2008) Young, Simon; Mikos, Antonios G.
    Successful translation of experimental therapeutics to the clinical setting will require development of challenging in vivo models which mimic oral and craniofacial wound healing environments, and can accurately assess a construct's angiogenic and osteogenic performance. With the intent of developing an easily accessible and reproducible, non-healing alveolar bone defect in the rabbit, 10-mm diameter partial- and full thickness cylindrical defects were created in the premolar/molar region of the mandible. Microcomputed tomography (micro-CT) and histological analysis of the partial thickness defect demonstrated significant bone formation at 8 weeks, and complete union and contour regeneration at 16 weeks. In contrast, the full thickness defect was never able to bridge itself and only exhibited partial bone regeneration by 16 weeks, demonstrating the potential of the mandibular full thickness defect as a test bed for tissue engineering constructs. A subsequent study examined the use of contrast-enhanced micro-CT to characterize neovascularization in the rabbit alveolar bone defect model. Scaffold-implanted groups were found to have differences in vessel network morphology versus empty defects. These results suggest the rabbit alveolar bone defect model in conjunction with micro-CT imaging is a robust system for evaluating the angiogenic and osteogenic potential of tissue engineering constructs. Lastly, the scale-up to larger human applications will require rapid and adequate vascularization throughout implanted scaffolds, perhaps necessitating simultaneous delivery of angiogenic and osteogenic growth factors with specific release kinetics and dosages for effective tissue regeneration. A final study investigated the dose effect of simultaneous delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) for bone regeneration in a critical size rat cranial defect at 12 weeks. A dose-dependent decrease in percent bone formation was observed as BMP-2 alone decreased from 2 microg to 0.5-1 microg. The addition of VEGF in amounts of 6-12 microg was unable to reverse this decrease in bone formation, although improvements in bony bridging were seen in some of the dual release groups. Thus, further optimization of the growth factor doses and release kinetics may be required to observe long-term benefits over single growth factor release in this particular animal model.