Bachelor of Engineering, Central South University (2013)
Master of Engineering, Cornell University (2014)
Doctor of Philosophy, University of Florida (2020)
Ph.D., University of Florida, Medicine-Immunology (2020)
Master of Engineering, Cornell University, Biomedical Engineering (2015)
Bachelor of Engineering, Central South University, China, Bioengineering (2013)
Elizabeth Mellins, Postdoctoral Faculty Sponsor
Controlled Release of Anti-Inflammatory and Proangiogenic Factors from Macroporous Scaffolds.
Tissue engineering. Part A
The simultaneous local delivery of anti-inflammatory and proangiogenic agents via biomaterial scaffolds presents a promising method for improving the engraftment of tissue-engineered implants while avoiding potentially detrimental systemic delivery. In this study, polydimethylsiloxane (PDMS) microbeads were loaded with either anti-inflammatory dexamethasone (Dex) or proangiogenic 17β-estradiol (E2) and subsequently integrated into a single macroporous scaffold to create a controlled, dual-drug delivery platform. Compared to a standard monolithic drug dispersion scaffold, macroporous scaffolds containing drug-loaded microbeads exhibited reduced initial burst release and increased durability of drug release for both agents. The incubation of scaffolds with lipopolysaccharide (LPS)-stimulated M1 macrophages found that Dex suppressed the production of proinflammatory and proangiogenic factors when compared to drug-free control scaffolds; however, the coincubation of macrophages with Dex and E2 scaffolds restored their proangiogenic features. Following implantation, Dex-loaded microbead scaffolds (Dex-μBS) suppressed host cell infiltration and integration, when compared to controls. In contrast, the codelivery of dexamethasone with estrogen from the microbead scaffold (Dex+E2-μBS) dampened overall host cell infiltration, but restored graft vascularization. These results demonstrate the utility of a microbead scaffold approach for the controlled, tailored, and local release of multiple drugs from an open framework implant. It further highlights the complementary impacts of local Dex and E2 delivery to direct the healthy integration of implants, which has broad applications to the field of tissue engineering and regenerative medicine.
View details for DOI 10.1089/ten.TEA.2020.0287
View details for PubMedID 33403942
Immunosuppressive PLGA TGF-β1 Microparticles Induce Polyclonal and Antigen-Specific Regulatory T Cells for Local Immunomodulation of Allogeneic Islet Transplants.
Frontiers in immunology
2021; 12: 653088
Allogeneic islet transplantation is a promising cell-based therapy for Type 1 Diabetes (T1D). The long-term efficacy of this approach, however, is impaired by allorejection. Current clinical practice relies on long-term systemic immunosuppression, leading to severe adverse events. To avoid these detrimental effects, poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) were engineered for the localized and controlled release of immunomodulatory TGF-β1. The in vitro co-incubation of TGF-β1 releasing PLGA MPs with naïve CD4+ T cells resulted in the efficient generation of both polyclonal and antigen-specific induced regulatory T cells (iTregs) with robust immunosuppressive function. The co-transplantation of TGF-β1 releasing PLGA MPs and Balb/c mouse islets within the extrahepatic epididymal fat pad (EFP) of diabetic C57BL/6J mice resulted in the prompt engraftment of the allogenic implants, supporting the compatibility of PLGA MPs and local TGF-β1 release. The presence of the TGF-β1-PLGA MPs, however, did not confer significant graft protection when compared to untreated controls, despite measurement of preserved insulin expression, reduced intra-islet CD3+ cells invasion, and elevated CD3+Foxp3+ T cells at the peri-transplantation site in long-term functioning grafts. Examination of the broader impacts of TGF-β1/PLGA MPs on the host immune system implicated a localized nature of the immunomodulation with no observed systemic impacts. In summary, this approach establishes the feasibility of a local and modular microparticle delivery system for the immunomodulation of an extrahepatic implant site. This approach can be easily adapted to deliver larger doses or other agents, as well as multi-drug approaches, within the local graft microenvironment to prevent transplant rejection.
View details for DOI 10.3389/fimmu.2021.653088
View details for PubMedID 34122410
View details for PubMedCentralID PMC8190479
In vitro platform establishes antigen-specific CD8+ T cell cytotoxicity to encapsulated cells via indirect antigen recognition.
2020; 256: 120182
The curative potential of non-autologous cellular therapy is hindered by the requirement of anti-rejection therapy. Cellular encapsulation within nondegradable biomaterials has the potential to inhibit immune rejection, but the efficacy of this approach in robust preclinical and clinical models remains poor. While the responses of innate immune cells to the encapsulating material have been characterized, little attention has been paid to the contributions of adaptive immunity in encapsulated graft destabilization. Avoiding the limitations of animal models, we established an efficient, antigen-specific in vitro platform capable of delineating direct and indirect host T cell recognition to microencapsulated cellular grafts and evaluated their consequential impacts. Using ovalbumin (OVA) as a model antigen, we determined that alginate microencapsulation abrogates direct CD8+ T cell activation by interrupting donor-host interaction; however, indirect T cell activation, mediated by host antigen presenting cells (APCs) primed with shed donor antigens, still occurs. These activated T cells imparted cytotoxicity on the encapsulated cells, likely via diffusion of cytotoxic solutes. Overall, this platform delivers unique mechanistic insight into the impacts of hydrogel encapsulation on host adaptive immune responses, comprehensively addressing a long-standing hypothesis of the field. Furthermore, it provides an efficient benchtop screening tool for the investigation of new encapsulation methods and/or synergistic immunomodulatory agents.
View details for DOI 10.1016/j.biomaterials.2020.120182
View details for PubMedID 32599358
View details for PubMedCentralID PMC7480933
Engineering immunomodulatory biomaterials for type 1 diabetes
NATURE REVIEWS MATERIALS
2019; 4 (6): 429-450
A cure for type 1 diabetes (T1D) would help millions of people worldwide, but remains elusive thus far. Tolerogenic vaccines and beta cell replacement therapy are complementary therapies that seek to address aberrant T1D autoimmune attack and subsequent beta cell loss. However, both approaches require some form of systematic immunosuppression, imparting risks to the patient. Biomaterials-based tools enable localized and targeted immunomodulation, and biomaterial properties can be designed and combined with immunomodulatory agents to locally instruct specific immune responses. In this Review, we discuss immunomodulatory biomaterial platforms for the development of T1D tolerogenic vaccines and beta cell replacement devices. We investigate nano- and microparticles for the delivery of tolerogenic agents and autoantigens, and as artificial antigen presenting cells, and highlight how bulk biomaterials can be used to provide immune tolerance. We examine biomaterials for drug delivery and as immunoisolation devices for cell therapy and islet transplantation, and explore synergies with other fields for the development of new T1D treatment strategies.
View details for DOI 10.1038/s41578-019-0112-5
View details for Web of Science ID 000470655400009
View details for PubMedID 32617176
View details for PubMedCentralID PMC7332200
Oxygen generating biomaterial improves the function and efficacy of beta cells within a macroencapsulation device.
2019; 210: 1-11
Tissue-engineered devices have the potential to significantly improve human health. A major impediment to the success of clinically scaled transplants, however, is insufficient oxygen transport, which leads to extensive cell death and dysfunction. To provide in situ supplementation of oxygen within a cellular implant, we developed a hydrolytically reactive oxygen generating material in the form of polydimethylsiloxane (PDMS) encapsulated solid calcium peroxide, termed OxySite. Herein, we demonstrate, for the first time, the successful implementation of this in situ oxygen-generating biomaterial to support elevated cellular function and efficacy of macroencapsulation devices for the treatment of type 1 diabetes. Under extreme hypoxic conditions, devices supplemented with OxySite exhibited substantially elevated beta cell and islet viability and function. Furthermore, the inclusion of OxySite within implanted macrodevices resulted in the significant improvement of graft efficacy and insulin production in a diabetic rodent model. Translating to human islets at elevated loading densities further validated the advantages of this material. This simple biomaterial-based approach for delivering a localized and controllable oxygen supply provides a broad and impactful platform for improving the therapeutic efficacy of cell-based approaches.
View details for DOI 10.1016/j.biomaterials.2019.04.017
View details for PubMedID 31029812
View details for PubMedCentralID PMC6527135
Local delivery of fingolimod from three-dimensional scaffolds impacts islet graft efficacy and microenvironment in a murine diabetic model.
Journal of tissue engineering and regenerative medicine
2018; 12 (2): 393-404
The local delivery of immunosuppressive agents could significantly promote the success of islet transplantation for the treatment of Type 1 diabetes. Fingolimod, a clinically-approved sphingosine-1-phosphate receptor agonist, has been found to dampen allograft islet rejection in rodent models when delivered systemically. Herein, we engineered a platform for the local delivery of fingolimod by incorporating it within a macroporous polydimethylsiloxane (PDMS) scaffold specifically designed for islet transplantation. In vitro drug release studies quantifying kinetics confirmed sustained release within targeted dose levels for >7 days. Fingolimod-PDMS scaffolds containing syngeneic islets were subsequently transplanted into diabetic mice for examination of the effect of local fingolimod release on engraftment. Surprisingly, either delayed or abrogated efficacy was observed when scaffolds contained a dosage of fingolimod >0.5% w/w; despite drug release rates estimated at ~80-fold less than published systemic delivery reports where no detrimental effects were noted. Histological analysis of explants indicated a dose-dependent modulation of cellular migration and phenotype at the graft site, with high doses impairing host infiltration and engraftment while lower doses promoted leucocyte migration. Mechanistic in vivo and in vitro studies observed unique host and islet responses to local fingolimod delivery, with impairment of murine islet viability and function. Overall, this study confirmed the ability to modulate local delivery of fingolimod in a sustained-release manner using a three-dimensional PDMS scaffold; however, the observed detrimental impacts at the site of islet transplantation do not support further investigation of local delivery at the graft site in murine models.
View details for DOI 10.1002/term.2464
View details for PubMedID 28486786
Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer.
2017; 8 (37): 62131-62142
Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC. Reduction of the repressive epigenetic modification H3K27me2/3 correlates with PCa aggressiveness, while corresponding demethylases JMJD3/UTX are overexpressed in PCa. We found that JMJD3/UTX inhibitor GSK-J4 reduced more efficiently proliferation of AR-ΔLBD cells (CRPC model) compared with isogenic AR-WT cells. Inhibition of JMJD3/UTX protects demethylation of H3K27Me2/3, thus reducing levels of H3k27Me1. We observed that the reduction dynamics of H3K27Me1 was faster and achieved at lower inhibitor concentrations in AR-ΔLBD cells, suggesting that inhibition of JMJD3/UTX diminished proliferation of these cells by hindering AR-driven transcription. In addition, we observed synergy between GSK-J4 and Cabazitaxel, a taxane derivative that is approved for CRPC treatment. Collectively, our results point at the H3K27 demethylation pathway as a new potential therapeutic target in CRPC patients.
View details for DOI 10.18632/oncotarget.19100
View details for PubMedID 28977932
View details for PubMedCentralID PMC5617492