Publications by authors named "Nicholas A Peppas"

198 Publications

Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic.

Adv Drug Deliv Rev 2021 Oct 9;179:114000. Epub 2021 Oct 9.

Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA; Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA; Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX, USA. Electronic address:

mRNA vaccines have received major attention in the fight against COVID-19. Formulations from companies such as Moderna and BioNTech/Pfizer have allowed us to slowly ease the social distancing measures, mask requirements, and lockdowns that have been prevalent since early 2020. This past year's focused work on mRNA vaccines has catapulted this technology to the forefront of public awareness and additional research pursuits, thus leading to new potential for bionanotechnology principles to help drive further innovation using mRNA. In addition to alleviating the burden of COVID-19, mRNA vaccines could potentially provide long-term solutions all over the world for diseases ranging from influenza to AIDS. Herein, we provide a brief commentary based on the history and development of mRNA vaccines in the context of the COVID-19 pandemic. Furthermore, we address current research using the technology and future directions of mRNA vaccine research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2021.114000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502079PMC
October 2021

Electrostatic and Covalent Assemblies of Anionic Hydrogel-Coated Gold Nanoshells for Detection of Dry Eye Biomarkers in Human Tears.

Nano Lett 2021 Oct 8. Epub 2021 Oct 8.

Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, Texas 78712, United States.

Although dry eye is highly prevalent, many challenges exist in diagnosing the symptom and related diseases. For this reason, anionic hydrogel-coated gold nanoshells (AuNSs) were used in the development of a label-free biosensor for detection of high isoelectric point tear biomarkers associated with dry eye. A custom, aldehyde-functionalized oligo(ethylene glycol)acrylate (Al-OEGA) was included in the hydrogel coating to enhance protein recognition through the formation of dynamic covalent (DC) imine bonds with solvent-accessible lysine residues present on the surface of select tear proteins. Our results demonstrated that hydrogel-coated AuNSs, composed of monomers that form ionic and DC bonds with select tear proteins, greatly enhance protein recognition due to changes in the maximum localized surface plasmon resonance wavelength exhibited by AuNSs in noncompetitive and competitive environments. Validation of the developed biosensor in commercially available pooled human tears revealed the potential for clinical translation to establish a method for dry eye diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.1c02941DOI Listing
October 2021

Recent Advancements in Biosensing Approaches for Screening and Diagnostic Applications.

Curr Opin Biomed Eng 2021 Sep 29;19. Epub 2021 Jun 29.

Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.

Recent advancements in molecular recognition have provided additional diagnostic and treatment approaches for multiple diseases, including autoimmune disorders and cancers. Research investigating how the composition of biological fluids is altered during disease progression, including differences in the expression of the small molecules, proteins, RNAs, and other components present in patient tears, saliva, blood, urine, or other fluids, has provided a wealth of potential candidates for early disease screening; however, adoption of biomarker screening into clinical settings has been challenged by the need for more robust, low-cost, and high-throughput assays. This review examines current approaches in molecular recognition and biosensing for the quantification of biomarkers for disease screening and diagnostic outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cobme.2021.100318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389739PMC
September 2021

Solute Transport Dependence on 3D Geometry of Hydrogel Networks.

Macromol Chem Phys 2021 Aug 2;222(16). Epub 2021 Jul 2.

Department of Biomedical Engineering, University of Texas, Austin, TX 78712, USA.

Hydrogels are used in drug delivery applications, chromatography, and tissue engineering to control the rate of solute transport based on solute size and hydrogel-solute affinity. Ongoing modeling efforts to quantify the relationship between hydrogel properties, solute properties, and solute transport contribute toward an increasingly efficient hydrogel design process and provide fundamental insight into the mechanisms relating hydrogel structure and function. However, here we clarify previous conclusions regarding the use of mesh size in hydrogel transport models. We use 3D geometry and hydrogel network visualizations to show that mesh size and junction functionality both contribute to the mesh radius, which determines whether a solute can diffuse within a hydrogel. Using mesh radius instead of mesh size to model solute transport in hydrogels will correct junction functionality-dependent modeling errors, improving hydrogel design predictions and clarifying mechanisms of solute transport in hydrogels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/macp.202100138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389770PMC
August 2021

Lipid- and Polymer-Based Nanoparticle Systems for the Delivery of CRISPR/Cas9.

J Drug Deliv Sci Technol 2021 Oct 11;65. Epub 2021 Jul 11.

Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio, San Antonio, TX, USA.

The discovery of clustered regularly interspaced short palindromic repeat (CRISPR)/ CRISPR-associated (Cas) genome editing systems and their applications in human health and medicine has heralded a new era of biotechnology. However, the delivery of CRISPR therapeutics is arguably the most difficult barrier to overcome for translation to clinical administration. Appropriate delivery methods are required to efficiently and selectively transport all gene editing components to specific target cells and tissues of interest, while minimizing off-target effects. To overcome this challenge, we discuss and critic nanoparticle delivery strategies, focusing on the use of lipid-based and polymeric-based matrices herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jddst.2021.102728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318345PMC
October 2021

Innovations in Biomaterial Design toward Successful RNA Interference Therapy for Cancer Treatment.

Adv Healthc Mater 2021 07 11;10(13):e2100350. Epub 2021 May 11.

McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, 78712, USA.

Gene regulation using RNA interference (RNAi) therapy has been developed as one of the frontiers in cancer treatment. The ability to tailor the expression of genes by delivering synthetic oligonucleotides to tumor cells has transformed the way scientists think about treating cancer. However, its clinical application has been limited due to the need to deliver synthetic RNAi oligonucleotides efficiently and effectively to target cells. Advances in nanotechnology and biomaterials have begun to address the limitations to RNAi therapeutic delivery, increasing the likelihood of RNAi therapeutics for cancer treatment in clinical settings. Herein, innovations in the design of nanocarriers for the delivery of oligonucleotides for successful RNAi therapy are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202100350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273125PMC
July 2021

Cytocompatibility, membrane disruption, and siRNA delivery using environmentally responsive cationic nanogels.

J Control Release 2021 04 3;332:608-619. Epub 2021 Mar 3.

McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX 78712, USA; Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Ave. Stop A1900, Austin, TX 78712, USA; Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX 78712, USA; Departments of Pediatrics, Surgery, and Perioperative Care, Dell Medical School, 1601 Trinity St., Bldg. B, Stop Z0800, Austin, TX 78712, USA. Electronic address:

Advances in the formulation of nucleic acid-based therapeutics have rendered them a promising avenue for treating diverse ailments. Nonetheless, clinical translation of these therapies is hindered by a lack of strategies to ensure the delivery of these nucleic acids in a safe, efficacious manner with the required spatial and temporal control. To this aim, environmentally responsive hydrogels are of interest due to their ability to provide the desired characteristics of a protective carrier for siRNA delivery. Previous work in our laboratory has demonstrated the ability to synthesize nanoparticle formulations with targeted pK, swelling, and surface PEG density. Here, a library of nanoparticle formulations was assessed on their in vitro toxicity, hemolytic capacity, siRNA loading, and gene-silencing efficacy. Successful candidates exhibited the lowest degrees of cytotoxicity, pH-dependent membrane disruption potential, the highest siRNA loading, and the highest transfection efficacies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089052PMC
April 2021

Miniaturized Needle Array-Mediated Drug Delivery Accelerates Wound Healing.

Adv Healthc Mater 2021 04 15;10(8):e2001800. Epub 2021 Feb 15.

Department of Biomedical Engineering, University of Connecticut, Farmington, CT, 06030, USA.

A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202001800DOI Listing
April 2021

A combinational chemo-immune therapy using an enzyme-sensitive nanoplatform for dual-drug delivery to specific sites by cascade targeting.

Sci Adv 2021 Feb 5;7(6). Epub 2021 Feb 5.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78731, USA.

Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aba0776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864565PMC
February 2021

Polymer Composition Primarily Determines the Protein Recognition Characteristics of Molecularly Imprinted Hydrogels.

J Mater Chem B 2020 09 22;8(34):7685-7695. Epub 2020 Jul 22.

Department of Biomedical Engineering, University of Texas, Austin, TX, 78712, USA.

Synthetic hydrogels with the ability to recognize and bind target proteins are useful for a number of applications, including biosensing and therapeutic agent delivery. One popular method for fabricating recognitive hydrogels is molecular imprinting. A long-standing hypothesis of the field is that these molecularly imprinted polymers (MIPs) retain the chemical and geometric profile of their protein template, resulting in subsequent ability to recognize the template in solution. Here, we systematically determined the influence of network composition, as well as the identity, amount, and extraction of imprinting templates, on the protein binding of MIPs. Network composition (i.e. the relative number of ionizable and hydrophobic groups) explained the extent of protein adsorption in all cases. The identity and amount of imprinting template, albeit a protein or synthetic polymer (PEG) of similar molecular weight, did not significantly influence the amount of protein bound. While the purification method influenced the extent of template adsorption, it did so by chemically modifying the network (acrylamide hydrolysis, increasing the acid content by up to 21%) and not by voiding occupied MIP pores. Therefore, our results indicate that material composition determines the extent to which MIPs bind template and non-template proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/D0TB01627FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807727PMC
September 2020

Introduction.

Tissue Eng Part A 2020 12;26(23-24):1224-1225

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ten.tea.2020.29021.introDOI Listing
December 2020

Engineering precision nanoparticles for drug delivery.

Nat Rev Drug Discov 2021 02 4;20(2):101-124. Epub 2020 Dec 4.

Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41573-020-0090-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717100PMC
February 2021

Peptide conjugation enhances the cellular co-localization, but not endosomal escape, of modular poly(acrylamide-co-methacrylic acid) nanogels.

J Control Release 2021 01 27;329:1162-1171. Epub 2020 Oct 27.

Department of Biomedical Engineering, University of Texas, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, University of Texas, Austin, TX 78712, USA; Institute for Biomaterials, Drug Delivery, and Regenerative Medicine University of Texas, Austin, TX 78705, USA; Department of Pediatrics, Dell Medical School, Austin, TX 78712, USA; Department of Surgery and Perioperative Care, Dell Medical School, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of Texas, Austin, TX 78712, USA. Electronic address:

Nanoparticles must recognize, adhere to, and/or traverse multiple barriers in sequence to achieve cytosolic drug delivery. New nanoparticles often exhibit a unique ability to cross a single barrier (i.e. the vasculature, cell membrane, or endosomal compartment), but fail to deliver an adequate dose to intracellular sites of action because they cannot traverse other biological barriers for which they were not optimized. Here, we developed poly(acrylamide-co-methacrylic acid) nanogels that were modified in a modular manner with bioactive peptides. This nanogel does not recognize target cells or disrupt endosomal vesicles in its unmodified state, but can incorporate peptides with molecular recognition or environmentally responsive properties. Nanogels were modified with up to 15 wt% peptide without significantly altering their size, surface charge, or stability in aqueous buffer. Nanogels modified with a colon cancer-targeting oligopeptide exhibited up to a 324% enhancement in co-localization with SW-48 colon cancer cells in vitro, while influencing nanogel uptake by fibroblasts and macrophages to a lesser extent. Nanogels modified with an endosome disrupting peptide failed to retain its native endosomolytic activity, when coupled either individually or in combination with the targeting peptide. Our results offer a proof-of-concept for modifying synthetic nanogels with a combination of peptides that address barriers to cytosolic delivery individually and in tandem. Our data further motivate the need to identify endosome disrupting moieties which retain their activity within poly(acidic) networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2020.10.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904656PMC
January 2021

Recent Advances in Smart Biomaterials for the Detection and Treatment of Autoimmune Diseases.

Adv Funct Mater 2020 Sep 13;30(37). Epub 2020 Mar 13.

McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712.

Autoimmune diseases are a group of debilitating illnesses that are often idiopathic in nature. The steady rise in the prevalence of these conditions warrants new approaches for diagnosis and treatment. Stimuli-responsive biomaterials also known as "smart", "intelligent" or "recognitive" biomaterials are widely studied for their applications in drug delivery, biosensing and tissue engineering due to their ability to produce thermal, optical, chemical, or structural changes upon interacting with the biological environment. This critical analysis highlights studies within the last decade that harness the recognitive capabilities of these biomaterials towards the development of novel detection and treatment options for autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adfm.201909556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566744PMC
September 2020

A tumor-to-lymph procedure navigated versatile gel system for combinatorial therapy against tumor recurrence and metastasis.

Sci Adv 2020 Sep 4;6(36). Epub 2020 Sep 4.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.

Application of cancer vaccines is limited due to their systemic immunotoxicity and inability to satisfy all the steps, including loading of tumor antigens, draining of antigens to lymph nodes (LNs), internalization of antigens by dendritic cells (DCs), DC maturation, and cross-presentation of antigens for T cell activation. Here, we present a combinatorial therapy, based on a α-cyclodextrin (CD)-based gel system, DOX/ICG/CpG-P-ss-M/CD, fabricated by encapsulating doxorubicin (DOX) and the photothermal agent indocyanine green (ICG). Upon irradiation, the gel system exhibited heat-responsive release of DOX and vaccine-like nanoparticles, CpG-P-ss-M, along with chemotherapy- and phototherapy-generated abundant tumor-specific antigen storage in situ. The released CpG-P-ss-M acted as a carrier adsorbed and delivered antigens to LNs, promoting the uptake of antigens by DCs and DC maturation. Notably, combined with PD-L1 blocking, the therapy effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abb3116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473750PMC
September 2020

CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy.

Adv Drug Deliv Rev 2020 21;158:17-35. Epub 2020 Jul 21.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Departments of Pediatrics and Surgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

Genetically engineered immune cells with chimeric antigen receptors (CAR) or modified T cell receptors (TCR) have demonstrated their potential as a potent class of new cancer therapeutic strategy. Despite the clinical success of autologous CD19 CAR T cells in hematological malignancies, allogeneic T cells exhibit many advantages over their autologous counterparts and have recently gathered widespread attention due to the emergence of multiplex genome editing techniques, particularly CRISPR/Cas systems. Furthermore, genetically engineered T cells face a host of major challenges in solid tumors that are not as significant for blood cancers such as T cell targeted delivery, target specificity, proliferation, persistence, and the immunosuppressive tumor microenvironment. We take this opportunity to analyze recent strategies to develop allogeneic T cells, specifically in consideration of CRISPR/Cas and its delivery systems for multiplex gene editing. Additionally, we discuss the current methods used to delivery CRISPR/Cas systems for immunotherapeutic applications, and the challenges to continued development of novel delivery systems. We also provide a comprehensive analysis of the major challenges that genetically engineered T cells face in solid tumors along with the most recent strategies to overcome these barriers, with an emphasis on CRISPR-based approaches. We illustrate the synergistic prospects for how the combination of synthetic biology and immune-oncology could pave the way for designing the next generation of precision cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2020.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736063PMC
September 2021

Advanced engineered nanoparticulate platforms to address key biological barriers for delivering chemotherapeutic agents to target sites.

Adv Drug Deliv Rev 2020 12 1;167:170-188. Epub 2020 Jul 1.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Departments of Pediatrics and Surgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

The widespread development of nanocarriers to deliver chemotherapeutics to specific tumor sites has been motivated by the lack of selective targeting during chemotherapy inducing serious side effects and low therapeutic efficacy. The utmost challenge in targeted cancer therapies is the ineffective drug delivery system, in which the drug-loaded nanocarriers are hindered by multiple complex biological barriers that compromise the therapeutic efficacy. Despite considerable progress engineering novel nanoplatforms for the delivery of chemotherapeutics, there has been limited success in a clinical setting. In this review, we identify and analyze design strategies for improved therapeutic efficacy and unique properties of nanoplatforms, including liposomes, polymeric micelles, nanogels, and dendrimers. We provide a comprehensive and integral description of key biological barriers that nanoplatforms are exposed to during their in vivo journey and discuss associated strategies to overcome these barriers based on the latest research and information available in the field. We expect this review to provide constructive information for the rational design of more effective nanoplatforms to advance precision therapies and accelerate their clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2020.06.030DOI Listing
December 2020

Cell-laden alginate hydrogels for the treatment of diabetes.

Expert Opin Drug Deliv 2020 08;17(8):1113-1118

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU , Vitoria-Gasteiz, Spain.

Introduction: Diabetes mellitus is an ever-increasing medical condition that currently suffers 1 of 11 adults who may have lifelong commitment with insulin injections. Cell-laden hydrogels releasing insulin may provide the ultimate means of correcting diabetes. Here, we provide insights of this cell-based approach including latest preclinical and clinical progress both from academia and industry.

Area Covered: The present article focuses on reviewing latest advances in cell-laden hydrogels both from the technological and biological perspective. The most relevant clinical results including clinical trials are also discussed.

Expert Opinion: Current progress in technological issues (stem cells, devices, biomaterials) have contributed cell encapsulation science to have a very relevant progress in the field of diabetes treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2020.1778667DOI Listing
August 2020

Nanogel receptors for high isoelectric point protein detection: influence of electrostatic and covalent polymer-protein interactions.

Chem Commun (Camb) 2020 Jun 4;56(45):6141-6144. Epub 2020 May 4.

Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA.

An aldehyde acrylate-based functional monomer was incorporated into poly(N-isopropylacrylamide-co-methacrylic acid) nanogels for use as protein receptors. The aldehyde component forms dynamic imines with surface exposed lysine residues, while carboxylic acid/carboxylate moieties form electrostatic interactions with high isoelectric point proteins. Together, these interactions effect protein adsorption and recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cc02200dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377432PMC
June 2020

Degradable Poly(Methyl Methacrylate)-co-Methacrylic Acid Nanoparticles for Controlled Delivery of Growth Factors for Bone Regeneration.

Tissue Eng Part A 2020 12 14;26(23-24):1226-1242. Epub 2020 Apr 14.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA.

Bone tissue engineering strategies have been developed to address the limitations of the current gold standard treatment options for bone-related disorders. These systems consist of an engineered scaffold that mimics the extracellular matrix and provides an architecture to guide the natural bone regeneration process, and incorporated growth factors that enhance cell recruitment and ingress into the scaffold and promote the osteogenic differentiation of stem cells and angiogenesis. In particular, the osteogenic growth factor bone morphogenetic protein 2 (BMP-2) has been widely studied as a potent agent to improve bone regeneration. A key challenge in growth factor delivery is that the growth factors must reach their target sites without losing bioactivity and remain in the location for an extended period to effectively aid in the formation of new bone. Protein incorporation into nanoparticles can both protect protein bioactivity and enable its sustained release. In this study, a poly(methyl methacrylate-co-methacrylic acid) nanoparticle-based system was synthesized incorporating a custom poly(ethylene glycol) dimethacrylate crosslinker. It was demonstrated that the nanoparticle degradation rate can be controlled by tuning the number of hydrolytically degradable ester units along the crosslinker. We also showed that the nanoparticles had high affinity for a model protein for BMP-2, and optimal conditions for maximum protein loading efficiency were elucidated. Ultimately, the proposed system and its high degree of tunability can be applied to a wide range of growth factors and tissue engineering applications. Impact Statement In this study, we developed a novel method of synthesizing nanoparticles with tunable degradation rates through the incorporation of a custom synthesized, hydrolytically degradable crosslinker. In addition, we demonstrated the affinity of the synthesized nanoparticles for a model protein for bone morphogenetic protein 2 (BMP-2). The tunability of these nanoparticles can be used to develop complex tissue engineering systems, for example, for the delivery of multiple growth factors involved at different stages of the bone regeneration process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ten.tea.2020.0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757707PMC
December 2020

Optimization of Cationic Nanogel PEGylation to Achieve Mammalian Cytocompatibility with Limited Loss of Gram-Negative Bactericidal Activity.

Biomacromolecules 2020 04 2;21(4):1528-1538. Epub 2020 Apr 2.

The LaMontagne Center for Infectious Disease, Austin, Texas 78712, United States.

Tuning the composition of antimicrobial nanogels can significantly alter both nanogel cytotoxicity and antibacterial activity. This project investigated the extent to which PEGylation of cationic, hydrophobic nanogels altered their cytotoxicity and bactericidal activity. These biodegradable, cationic nanogels were synthesized by activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) emulsion polymerization with up to 13.9 wt % PEG (MW = 2000) MA, as verified by H NMR. Nanogel bactericidal activity was assessed against Gram-negative and and Gram-positive and by measuring membrane lysis with a LIVE/DEAD assay. and viability was further validated by measuring metabolic activity with a PrestoBlue assay and imaging bacteria stained with a LIVE/DEAD probe. All tested nanogels decreased the membrane integrity (0.5 mg/mL dose) for Gram-negative and , irrespective of the extent of PEGylation. PEGylation (13.9 wt %) increased the cytocompatibility of cationic nanogels toward RAW 264.7 murine macrophages and L929 murine fibroblasts by over 100-fold, relative to control nanogels. PEGylation (42.8 wt %) reduced nanogel uptake by 43% for macrophages and 63% for fibroblasts. Therefore, PEGylation reduced nanogel toxicity to mammalian cells without significantly compromising their bactericidal activity. These results facilitate future nanogel design for perturbing the growth of Gram-negative bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biomac.0c00081DOI Listing
April 2020

Modular Fabrication of Intelligent Material-Tissue Interfaces for Bioinspired and Biomimetic Devices.

Prog Mater Sci 2019 Dec 17;106. Epub 2019 Jul 17.

Department of Biomedical Engineering, the University of Texas at Austin, Austin, Texas, USA.

One of the goals of biomaterials science is to reverse engineer aspects of human and nonhuman physiology. Similar to the body's regulatory mechanisms, such devices must transduce changes in the physiological environment or the presence of an external stimulus into a detectable or therapeutic response. This review is a comprehensive evaluation and critical analysis of the design and fabrication of environmentally responsive cell-material constructs for bioinspired machinery and biomimetic devices. In a bottom-up analysis, we begin by reviewing fundamental principles that explain materials' responses to chemical gradients, biomarkers, electromagnetic fields, light, and temperature. Strategies for fabricating highly ordered assemblies of material components at the nano to macro-scales via directed assembly, lithography, 3D printing and 4D printing are also presented. We conclude with an account of contemporary material-tissue interfaces within bioinspired and biomimetic devices for peptide delivery, cancer theranostics, biomonitoring, neuroprosthetics, soft robotics, and biological machines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pmatsci.2019.100589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079701PMC
December 2019

Immobilization of nanocarriers within a porous chitosan scaffold for the sustained delivery of growth factors in bone tissue engineering applications.

J Biomed Mater Res A 2020 05 29;108(5):1122-1135. Epub 2020 Jan 29.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas.

To guide the natural bone regeneration process, bone tissue engineering strategies rely on the development of a scaffold architecture that mimics the extracellular matrix and incorporates important extracellular signaling molecules, which promote fracture healing and bone formation pathways. Incorporation of growth factors into particles embedded within the scaffold can offer both protection of protein bioactivity and a sustained release profile. In this work, a novel method to immobilize carrier nanoparticles within scaffold pores is proposed. A biodegradable, osteoconductive, porous chitosan scaffold was fabricated via the "freeze-drying method," leading to scaffolds with a storage modulus of 8.5 kPa and 300 μm pores, in line with existing bone scaffold properties. Next, poly(methyl methacrylate-co-methacrylic acid) nanoparticles were synthesized and immobilized to the scaffold via carbodiimide-crosslinker chemistry. A fluorescent imaging study confirmed that the conventional methods of protein and nanocarrier incorporation into scaffolds can lead to over 60% diffusion out of the scaffold within the first 5 min of implantation, and total disappearance within 4 weeks. The novel method of nanocarrier immobilization to the scaffold backbone via carbodiimide-crosslinker chemistry allows full retention of particles for up to 4 weeks within the scaffold bulk, with no negative effects on the viability and proliferation of human umbilical vein endothelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm.a.36887DOI Listing
May 2020

Molecular recognition with soft biomaterials.

Soft Matter 2020 Jan 14;16(4):856-869. Epub 2020 Jan 14.

Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX 78712, USA. and McKetta Department of Chemical Engineering, The University of Texas at Austin, 200 E. Dean Keeton St. Stop C0400, Austin, TX 78712, USA and Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX 78712, USA and Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Ave. Stop A1900, Austin, TX 78712, USA and Department of Surgery and Perioperative Care, Dell Medical School, 1601 Trinity St., Bldg. B, Stop Z0800, Austin, TX 78712, USA and Department of Pediatrics, Dell Medical School, 1400 Barbara Jordan Blvd., Austin, TX 7872, USA.

Biomacromolecules and engineered materials can achieve molecular recognition if they engage their ligand with properly oriented and chemically complementary moieties. Recently, there has been significant interest in fabricating recognitive soft materials, which possess specific affinity for biological analytes. We present a summary and evaluation of current recognitive materials for biosensing, drug delivery, and regenerative medicine applications. We highlight the impact of material composition on the extent and specificity of ligand adsorption, citing new theoretical and empirical evidence. We conclude with a guide for synthesizing and characterizing novel recognitive materials, as well as recommendations for ligand selection and experimental design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9sm01981bDOI Listing
January 2020

Developing a Multidisciplinary Approach for Engineering Stem Cell Organoids.

Ann Biomed Eng 2020 Jul 28;48(7):1895-1904. Epub 2019 Oct 28.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.

Recent advances in stem cell biology, synthetic biology, bioengineering, and biotechnology have included significant work leading to the development of stem cell-derived organoids. The growing popularity of organoid research and use of organoids is widely due to the fact that these three-dimensional cellular structures better model human physiology compared to traditional in vitro and in vivo methods by recapitulating many biologically relevant parameters. Organoids show great promise for a wide range of applications, such as for use in disease modeling, drug discovery, and regenerative medicine. However, many challenges associated with reproducibility and scale up still remain. Identification of the conditions which generate a robust environment that predictably promotes cellular self-assembly and organization leading to organoid formation is critical and requires a multidisciplinary approach. To accomplish this we need to identify a cellular source, engineer a matrix to stimulate cell-cell and cell-matrix interactions, and provide the biochemical and biophysical cues which mimic that of the in vivo environment. Discussion of the components needed for organoid development and formation is reviewed herein, as well as specific organoid examples and the promise of this research for the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10439-019-02391-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186139PMC
July 2020

Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications.

Sci Adv 2019 09 27;5(9):eaax7946. Epub 2019 Sep 27.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.

Formulations and devices for precision medicine applications must be tunable and multiresponsive to treat heterogeneous patient populations in a calibrated and individual manner. We engineered modular poly(acrylamide-co-methacrylic acid) copolymers, cross-linked into multiresponsive nanogels with either a nondegradable or degradable disulfide cross-linker, that were customized via orthogonal chemistries to target biomarkers of an individual patient's disease or deliver multiple therapeutic modalities. Upon modification with functional small molecules, peptides, or proteins, these nanomaterials delivered methylene blue with environmental responsiveness, transduced visible light for photothermal therapy, acted as a functional enzyme, or promoted uptake by cells. In addition to quantifying the nanogels' composition, physicochemical characteristics, and cytotoxicity, we used a QCM-D method for characterizing nanomaterial degradation and a high-throughput assay for cellular uptake. In conclusion, we generated a tunable nanogel composition for precision medicine applications and new quantitative protocols for assessing the bioactivity of similar platforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aax7946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764836PMC
September 2019

Soft-Nanoparticle Functionalization of Natural Hydrogels for Tissue Engineering Applications.

Adv Healthc Mater 2019 09 12;8(18):e1900506. Epub 2019 Aug 12.

Department of Mechanical and Materials Engineering, University of Nebraska, Lincoln, NE, 68508, USA.

Tissue engineering has emerged as an important research area that provides numerous research tools for the fabrication of biologically functional constructs that can be used in drug discovery, disease modeling, and the treatment of diseased or injured organs. From a materials point of view, scaffolds have become an important part of tissue engineering activities and are usually used to form an environment supporting cellular growth, differentiation, and maturation. Among various materials used as scaffolds, hydrogels based on natural polymers are considered one of the most suitable groups of materials for creating tissue engineering scaffolds. Natural hydrogels, however, do not always provide the physicochemical and biological characteristics and properties required for optimal cell growth. This review discusses the properties and tissue engineering applications of widely used natural hydrogels. In addition, methods of modulation of their physicochemical and biological properties using soft nanoparticles as fillers or reinforcing agents are presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201900506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752977PMC
September 2019

Quantum dots in biomedical applications.

Acta Biomater 2019 08 11;94:44-63. Epub 2019 May 11.

McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA; Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA; Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA. Electronic address:

Semiconducting nanoparticles, more commonly known as quantum dots, possess unique size and shape dependent optoelectronic properties. In recent years, these unique properties have attracted much attention in the biomedical field to enable real-time tissue imaging (bioimaging), diagnostics, single molecule probes, and drug delivery, among many other areas. The optical properties of quantum dots can be tuned by size and composition, and their high brightness, resistance to photobleaching, multiplexing capacity, and high surface-to-volume ratio make them excellent candidates for intracellular tracking, diagnostics, in vivo imaging, and therapeutic delivery. We discuss recent advances and challenges in the molecular design of quantum dots are discussed, along with applications of quantum dots as drug delivery vehicles, theranostic agents, single molecule probes, and real-time in vivo deep tissue imaging agents. We present a detailed discussion of the biodistribution and toxicity of quantum dots, and highlight recent advances to improve long-term stability in biological buffers, increase quantum yield following bioconjugation, and improve clearance from the body. Last, we present an outlook on future challenges and strategies to further advance translation to clinical application. STATEMENT OF SIGNIFICANCE: Semiconducting nanoparticles, commonly known as quantum dots, possess unique size and shape dependent electrical and optical properties. In recent years, they have attracted much attention in biomedical imaging to enable diagnostics, single molecule probes, and real-time imaging of tumors. This review discusses recent advances and challenges in the design of quantum dots, and highlights how these strategies can further advance translation to clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2019.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642839PMC
August 2019

Tuning the biomimetic behavior of scaffolds for regenerative medicine through surface modifications.

J Tissue Eng Regen Med 2019 08 25;13(8):1275-1293. Epub 2019 Jun 25.

School of Chemical, Biological, and Materials Engineering, The University of Oklahoma, Norman, OK, USA.

Tissue engineering and regenerative medicine rely extensively on biomaterial scaffolds to support cell adhesion, proliferation, and differentiation physically and chemically in vitro and in vivo. Changes to the surface characteristics of the scaffolds have the greatest impact on cell response. Here, we discuss five dominant surface modification approaches used to biomimetically improve the most common scaffolds for tissue engineering, those based on aliphatic polyesters. Scaffolds of aliphatic polyesters such as poly(l-lactic acid), poly(l-lactic-co-glycolic acid), and poly(ε-caprolactone) are often used in tissue engineering because they provide desirable, tunable properties such as ease of manufacturing, good mechanical properties, and nontoxic degradation products. However, cell-surface interactions necessary for tissue engineering are limited on these materials by their smooth postfabrication surfaces, hydrophobicity, and lack of recognizable biochemical binding sites. The surface modification techniques that have been developed for synthetic polymer scaffolds reduce initial barriers to cell adhesion, proliferation, and differentiation. Topographical modification, protein adsorption, mineral coating, functional group incorporation, and biomacromolecule immobilization each contribute through varying mechanisms to improving cell interactions with aliphatic polyester scaffolds. Furthermore, rational combination of methods from these categories can provide nuanced, specific environments for targeted tissue development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/term.2859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715496PMC
August 2019

Control of Cationic Nanogel PEGylation in Heterogeneous ARGET ATRP Emulsion Polymerization with PEG Macromonomers.

J Polym Sci A Polym Chem 2018 Jul 7;56(14):1536-1544. Epub 2018 May 7.

McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas 78712.

Crosslinked cationic nanoscale networks with hydrophobic cores are an environmentally robust alternative to self-assembled polymeric drug delivery carriers with respect to therapeutic encapsulation and stability to dilution. However, the ability to tune the degree of PEG incorporated into nanogels during synthesis is more challenging. In this work, biodegradable cationic nanogels were synthesized by ARGET ATRP emulsion polymerization in a single step. The density of PEG in the final nanogels ranged from zero to 40 wt % and was dependent on the feed concentration of PEG monomer, surfactant concentration, surfactant hydrophilic-lipophilic balance, and the ratio of cationic to nonionic surfactant. A comprehensive analysis of nanogel material properties as a function of PEG graft density is presented including analysis of composition, monomer conversion, thermal properties, size, surface charge, and degradation. This study provides a robust analysis for the synthesis of degradable cationic nanogels via a controlled radical polymerization with predictable degrees of PEGylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pola.29035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426315PMC
July 2018
-->