Abstract:
:Gene therapies have great potential in regenerative medicine; however, clinical translation has been inhibited by low stability and limited transfection efficiencies. Herein, we incorporate collagen-mimetic peptide (CMP)-linked polyplexes in collagen scaffolds to increase DNA stability by up to 400% and enable tailorable in vivo transgene expression at 100-fold higher levels and 10-fold longer time periods. These improvements were directly linked to a sustained interaction between collagen and polyplexes that persisted during cellular remodeling, polyplex uptake, and intracellular trafficking. Specifically, incorporation of CMPs into polyethylenimine (PEI) polyplexes preserved serum-exposed polyplex-collagen activity over a period of 14days, with 4 orders-of-magnitude more intact DNA present in CMP-modified polyplex-collagen relative to unmodified polyplex-collagen after a 10day incubation under cell culture conditions. CMP-modification also altered endocytic uptake, as indicated by gene silencing studies showing a nearly 50% decrease in transgene expression in response to caveolin-1 silencing in modified samples versus only 30% in unmodified samples. Furthermore, cellular internalization studies demonstrated that polyplex-collagen association persisted within cells in CMP polyplexes, but not in unmodified polyplexes, suggesting that CMP linkage to collagen regulates intracellular transport. Moreover, experiments in an in vivo repair model showed that CMP modification enabled tailoring of transgene expression from 4 to 25days over a range of concentrations. Overall, these findings demonstrate that CMP decoration provides substantial improvements in gene retention, altered release kinetics, improved serum-stability, and improved gene activity in vivo. This versatile technique has great potential for multiple applications in regenerative medicine. STATEMENT OF SIGNIFICANCE:In this work, we demonstrate a novel approach for stably integrating DNA into collagen scaffolds to exploit the natural process of collagen remodelling for high efficiency non-viral gene delivery. The incorporation of CMPs into DNA polyplexes, coupled with the innate affinity between CMPs and collagen, not only permitted improved control over polyplex retention and release, but also provided a series of substantial and highly unique benefits via the stable and persistent linkage between CMP-polyplexes and collagen fragments. Specifically, CMP-modification of polyplexes was demonstrated to (i) control release for nearly a month, (ii) improve vector stability under physiological-like conditions, and (iii) provide ligands able to efficiently transfer genes via endocytic collagen pathways. These unique properties overcome key barriers inhibiting non-viral gene therapy.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Urello MA,Kiick KL,Sullivan MOdoi
10.1016/j.actbio.2017.08.038subject
Has Abstractpub_date
2017-10-15 00:00:00pages
167-178eissn
1742-7061issn
1878-7568pii
S1742-7061(17)30551-2journal_volume
62pub_type
杂志文章abstract::Chitosan was functionalized with imidazole moieties (CHimi) with the aim of improving its buffering capacity and promoting the endosomal escape ability of chitosan-DNA complexes, ultimately increasing their transfection efficiency. 5.6%, 12.9% and 22.1% of the glucosamine residues of chitosan were substituted. Complex...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.04.021
更新日期:2009-10-01 00:00:00
abstract::Cell-instructive hydrogels are attractive for skin repair and regeneration, serving as interactive matrices to promote cell adhesion, cell-driven remodeling and de novo deposition of extracellular matrix components. This paper describes the synthesis and photocrosslinking of cell-instructive pectin hydrogels using cel...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.11.016
更新日期:2018-01-15 00:00:00
abstract::The present study focuses on apatite coating on collagen films, with various different densities of carboxyl groups, using an alternate soaking process. Anionic collagen (AC), which has different densities of carboxylic groups compared to native collagen (NC), was obtained by hydrolysis of carboxyamides of asparagine ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2007.02.008
更新日期:2007-09-01 00:00:00
abstract::This study aimed to investigate the fluoride release properties and the effect on bond strength of two experimental adhesive cements. Synthesized particles of nano-fluorapatite (nano-FA) or nano-fluorohydroxyapatite (nano-FHA) were incorporated into a resin-modified glass ionomer cement (Fuji Ortho LC) and characteriz...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.10.029
更新日期:2011-03-01 00:00:00
abstract::The rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading con...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.06.024
更新日期:2017-09-15 00:00:00
abstract::The control of cell behaviour through material geometry is appealing as it avoids the requirement for complex chemical surface modifications. Significant advances in new technologies have been made to the development of polymeric biomaterials with controlled geometry and physico-chemical properties. Solution blow spin...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.01.020
更新日期:2017-03-15 00:00:00
abstract::Natural polymer materials have attracted great attention in the field of hemostasis because of their wide range of source, nontoxicity, hydrophilicity, and air permeability. In the present study, two natural polymers composed of carboxymethyl chitosan (CMCS) and sodium carboxymethylcellulose (CMCNa) plus γ-(2,3-epoxyp...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.07.043
更新日期:2020-09-15 00:00:00
abstract::Traumatic brain injury (TBI) is a life-threatening condition defined by internal brain herniation. Severe TBI is commonly treated by a two-stage surgical intervention, where decompressive craniectomy is first conducted to remove a large portion of calvarial bone and allow unimpeded brain swelling. In the second surger...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2018.02.013
更新日期:2018-04-15 00:00:00
abstract::We here present the first successful report on combining nanostructured silk and poly(ε-caprolactone) (PCL) with a ceramic scaffold to produce a composite scaffold that is highly porous (porosity ∼85%, pore size ∼500 μm, ∼100% interconnectivity), strong and non-brittle with a surface that resembles extracellular matri...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.10.009
更新日期:2012-01-01 00:00:00
abstract::A rapidly expanding literature broadly documents the impact of biophysical cues on cellular behaviors. In spite of increasing research efforts in this field, the underlying signaling processes are poorly understood. One of the candidate molecules for being involved in mechanotransduction is focal adhesion kinase (FAK)...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.07.004
更新日期:2012-12-01 00:00:00
abstract::Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.05.040
更新日期:2020-09-01 00:00:00
abstract::In this study, one-step enzyme-mediated preparation of a multi-functional injectable hyaluronic-acid-based hydrogel system is reported. Hydrogel was formed through the in situ coupling of phenol moieties by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2), and bioactive peptides were simultaneously conjugated...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2014.02.022
更新日期:2014-06-01 00:00:00
abstract::Functionalization of polymeric biomaterials permits the conjugation of cell signaling molecules capable of directing cell function. In this study, l-phenylalanine and l-aspartic acid were used to synthesize poly(ester amide)s (PEAs) with pendant carboxylic acid groups through an interfacial polycondensation approach. ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2014.04.014
更新日期:2014-08-01 00:00:00
abstract::Light curable methacrylate dental monomers containing reactive calcium phosphate filler (monocalcium phosphate monohydrate (MCPM) with particle diameter of 29 or 90microm) and beta-tricalcium phosphate (beta-TCP) at 1:1 weight ratio in a powder:liquid ratio (PLR) of 1:1 or 3:1 and chlorhexidine diacetate (0 or 5 wt.%)...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.03.030
更新日期:2009-09-01 00:00:00
abstract::Chitosan membranes were modified with mouse epidermal growth factor (EGF) by a photochemical technique. Photochemical immobilization was performed via a two-step process, in which EGF was first reacted with a heterobifunctional cross-linker sulfo-SANPAH (sulfosuccinimidyl 6(4'-azido-2'-nitrophenyl-amino)hexanoate) and...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2008.02.003
更新日期:2008-07-01 00:00:00
abstract::The poor delivery of nanoparticles to target cancer cells hinders their success in the clinical setting. In this work, an alternative target readily available for circulating nanoparticles has been selected to eliminate the need for nanoparticle penetration in the tissue: the tumor blood vessels. A tumor endothelium-t...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2019.11.004
更新日期:2020-01-01 00:00:00
abstract::Flax seeds produce mucilage after wetting. The mucilage due to its ability to absorb and maintain water is responsible for specific surface properties which are essential for seed dispersal in different ways. In the present paper, we asked how the hydration level affects the adhesive and frictional properties of the m...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.01.042
更新日期:2015-04-01 00:00:00
abstract::This study concerns the preparation and in vitro characterization of an apatite-wollastonite-2M bioactive glass ceramic which is intended to be used for the regeneration of hard tissue (i.e. in dental and craniomaxillofacial surgery). This bioglass ceramic has been obtained by appropriate thermal treatment through the...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.12.027
更新日期:2010-06-01 00:00:00
abstract::Macrophages represent a large component of the tumour microenvironment and are described to establish interactions with cancer cells, playing crucial roles in several stages of cancer progression. The functional plasticity of macrophages upon stimulation from the environment makes them susceptible to the influence of ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.05.022
更新日期:2015-09-01 00:00:00
abstract::Biodegradable PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) nanoparticles containing insulin phospholipid complex were loaded in chitosan-based thermosensitive hydrogels for long-term sustained and controlled delivery of insulin. The injectable hydrogels, prepared by adding β-glycerophosphate disodium salt (G...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.09.034
更新日期:2013-02-01 00:00:00
abstract::Magnetic N-benzyl-O-carboxymethylchitosan nanoparticles were synthesized through incorporation and in situ methods and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and magnetization measurements. Indomethacin was incorporated into the nanoparticles via...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.05.001
更新日期:2011-08-01 00:00:00
abstract::An important aim of bone regenerative medicine is to design biomaterials with controlled chemical and topographical features to guide stem cell fate towards osteoblasts without addition of specific osteogenic factors. Herein, we find that sprayed bioactive and biocompatible calcium phosphate substrates (CaP) with cont...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.11.042
更新日期:2017-02-01 00:00:00
abstract::There is an unmet need for improved, effective tissue engineering strategies to replace or repair bone damaged through disease or injury. Recent research has focused on developing biomaterial scaffolds capable of spatially and temporally releasing combinations of bioactive growth factors, rather than individual molecu...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2014.05.025
更新日期:2014-10-01 00:00:00
abstract::A new class of injectable and erodible hydrogels exhibiting highly robust gel strength at body temperature was fabricated by enzyme-mediated cross-linking between Pluronic copolymer micelles. Tyramine-conjugated Pluronic F-127 tri-block copolymers at two terminal ends of polyethylene oxide (PEO) side chains were synth...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.11.029
更新日期:2011-04-01 00:00:00
abstract::Antibody-mediated osseous regeneration (AMOR) has been proved as a promising strategy for osteogenic differentiation of induced pluripotent stem cells derived MSCs (iMSCs). The key characteristic of antibody that determines the AMOR potential is largely unknown. The glycosylation profile of immunoglobulin G (IgG) repr...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.07.055
更新日期:2020-09-15 00:00:00
abstract::Infection is one of the pivotal causes of nonunion in large bone defect after trauma or tumor resection. Three-dimensional (3D) composite scaffold with multifunctional-therapeutic properties offer many advantages over allogenic or xenogenic bone grafting for the restoration of challenging infected bone defects. In the...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2018.08.015
更新日期:2018-10-01 00:00:00
abstract::The objective was to evaluate the presence and distribution of the lubricating and anti-adhesion glycoprotein lubricin and cells containing the contractile isoform smooth muscle α-actin (SMA) in pseudomembranes around loose hip prostheses. Periprosthetic tissue was obtained at revision arthroplasty of eight aseptic, l...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.11.010
更新日期:2013-03-01 00:00:00
abstract:UNLABELLED:With improvements in oral health and an overall increase in quality of life, the percentage of fully or largely dentate seniors is increasing. Understanding the effects of aging on the mechanical properties of teeth is essential to the maintenance of lifelong oral health. In this investigation the effects of...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.12.038
更新日期:2016-03-01 00:00:00
abstract::The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion betw...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2018.02.011
更新日期:2018-04-15 00:00:00
abstract::N-glycans on IgG and IgM antibodies (Ab) facilitate Ab-mediated crosslinking of viruses and nanoparticles to the major structural elements of mucus and basement membranes. Nevertheless, the chemical moieties in these biological hydrogel matrices to which Ab can bind remain poorly understood. To gain insights into the ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.03.002
更新日期:2020-04-15 00:00:00