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1.  Enabling Surgical Placement of Hydrogels through Achieving Paste-Like Rheological Behavior in Hydrogel Precursor Solutions 
Annals of biomedical engineering  2015;43(10):2569-2576.
Hydrogels are a promising class of materials for tissue regeneration, but they lack the ability to be molded into a defect site by a surgeon because hydrogel precursors are liquid solutions that are prone to leaking during placement. Therefore, although the main focus of hydrogel technology and developments are on hydrogels in their crosslinked form, our primary focus is on improving the fluid behavior of hydrogel precursor solutions. In this work, we introduce a method to achieve paste-like hydrogel precursor solutions by combining hyaluronic acid nanoparticles with traditional crosslinked hyaluronic acid hydrogels. Prior to crosslinking, the samples underwent rheological testing to assess yield stress and recovery using linear hyaluronic acid as a control. The experimental groups containing nanoparticles were the only solutions that exhibited a yield stress, demonstrating that the nanoparticulate rather than the linear form of hyaluronic acid was necessary to achieve paste-like behavior. The gels were also photocrosslinked and further characterized as solids, where it was demonstrated that the inclusion of nanoparticles did not adversely affect the compressive modulus and that encapsulated bone marrow-derived mesenchymal stem cells remained viable. Overall, this nanoparticle-based approach provides a platform hydrogel system that exhibits a yield stress prior to crosslinking, and can then be crosslinked into a hydrogel that is capable of encapsulating cells that remain viable. This behavior may hold significant impact for hydrogel applications where a paste-like behavior is desired in the hydrogel precursor solution.
PMCID: PMC4540702  PMID: 25691398
Colloidal gel; yield stress; hyaluronic acid; nanoparticles
2.  Microsphere-based gradient implants for osteochondral regeneration: a long-term study in sheep 
Regenerative Medicine  2015;10(6):709-728.
The microfracture technique for cartilage repair has limited ability to regenerate hyaline cartilage.
The current study made a direct comparison between microfracture and an osteochondral approach with microsphere-based gradient plugs.
Materials & methods:
The PLGA-based scaffolds had opposing gradients of chondroitin sulfate and β-tricalcium phosphate. A 1-year repair study in sheep was conducted.
The repair tissues in the microfracture were mostly fibrous and had scattered fissures with degenerative changes. Cartilage regenerated with the gradient plugs had equal or superior mechanical properties; had lacunated cells and stable matrix as in hyaline cartilage.
This first report of gradient scaffolds in a long-term, large animal, osteochondral defect demonstrated potential for equal or better cartilage repair than microfracture.
PMCID: PMC4977000  PMID: 26418471
cartilage regeneration; chondroitin sulfate; gradients of signals; osteochondral tissue engineering; microfracture; microsphere-based scaffold
3.  Endochondral Ossification for Enhancing Bone Regeneration: Converging Native Extracellular Matrix Biomaterials and Developmental Engineering In Vivo 
Autologous bone grafting (ABG) remains entrenched as the gold standard of treatment in bone regenerative surgery. Consequently, many marginally successful bone tissue engineering strategies have focused on mimicking portions of ABG's “ideal” osteoconductive, osteoinductive, and osteogenic composition resembling the late reparative stage extracellular matrix (ECM) in bone fracture repair, also known as the “hard” or “bony” callus. An alternative, less common approach that has emerged in the last decade harnesses endochondral (EC) ossification through developmental engineering principles, which acknowledges that the molecular and cellular mechanisms involved in developmental skeletogenesis, specifically EC ossification, are closely paralleled during native bone healing. EC ossification naturally occurs during the majority of bone fractures and, thus, can potentially be utilized to enhance bone regeneration for nearly any orthopedic indication, especially in avascular critical-sized defects where hypoxic conditions favor initial chondrogenesis instead of direct intramembranous ossification. The body's native EC ossification response, however, is not capable of regenerating critical-sized defects without intervention. We propose that an underexplored potential exists to regenerate bone through the native EC ossification response by utilizing strategies which mimic the initial inflammatory or fibrocartilaginous ECM (i.e., “pro-” or “soft” callus) observed in the early reparative stage of bone fracture repair. To date, the majority of strategies utilizing this approach rely on clinically burdensome in vitro cell expansion protocols. This review will focus on the confluence of two evolving areas, (1) native ECM biomaterials and (2) developmental engineering, which will attempt to overcome the technical, business, and regulatory challenges that persist in the area of bone regeneration. Significant attention will be given to native “raw” materials and ECM-based designs that provide necessary osteo- and chondro-conductive and inductive features for enhancing EC ossification. In addition, critical perspectives on existing stem cell-based therapeutic strategies will be discussed with a focus on their use as an extension of the acellular ECM-based designs for specific clinical indications. Within this framework, a novel realm of unexplored design strategies for bone tissue engineering will be introduced into the collective consciousness of the regenerative medicine field.
PMCID: PMC4442558  PMID: 25336144
4.  Tailoring of processing parameters for sintering microsphere-based scaffolds with dense-phase carbon dioxide 
Microsphere-based polymeric tissue-engineered scaffolds offer the advantage of shape-specific constructs with excellent spatiotemporal control and interconnected porous structures. The use of these highly versatile scaffolds requires a method to sinter the discrete microspheres together into a cohesive network, typically with the use of heat or organic solvents. We previously introduced subcritical CO2 as a sintering method for microsphere-based scaffolds; here we further explored the effect of processing parameters. Gaseous or subcritical CO2 was used for making the scaffolds, and various pressures, ratios of lactic acid to glycolic acid in poly(lactic acid-co-glycolic acid), and amounts of NaCl particles were explored. By changing these parameters, scaffolds with different mechanical properties and morphologies were prepared. The preferred range of applied subcritical CO2 was 15–25 bar. Scaffolds prepared at 25 bar with lower lactic acid ratios and without NaCl particles had a higher stiffness, while the constructs made at 15 bar, lower glycolic acid content, and with salt granules had lower elastic moduli. Human umbilical cord mesenchymal stromal cells (hUCMSCs) seeded on the scaffolds demonstrated that cells penetrate the scaffolds and remain viable. Overall, the study demonstrated the dependence of the optimal CO2 sintering parameters on the polymer and conditions, and identified desirable CO2 processing parameters to employ in the sintering of microsphere-based scaffolds as a more benign alternative to heat-sintering or solvent-based sintering methods.
PMCID: PMC4474405  PMID: 23115065
microsphere-based scaffolds; subcritical CO2; PLGA; human umbilical cord mesenchymal stromal cells
5.  Decellularized Cartilage May Be a Chondroinductive Material for Osteochondral Tissue Engineering 
PLoS ONE  2015;10(5):e0121966.
Extracellular matrix (ECM)-based materials are attractive for regenerative medicine in their ability to potentially aid in stem cell recruitment, infiltration, and differentiation without added biological factors. In musculoskeletal tissue engineering, demineralized bone matrix is widely used, but recently cartilage matrix has been attracting attention as a potentially chondroinductive material. The aim of this study was thus to establish a chemical decellularization method for use with articular cartilage to quantify removal of cells and analyze the cartilage biochemical content at various stages during the decellularization process, which included a physically devitalization step. To study the cellular response to the cartilage matrix, rat bone marrow-derived mesenchymal stem cells (rBMSCs) were cultured in cell pellets containing cells only (control), chondrogenic differentiation medium (TGF-β), chemically decellularized cartilage particles (DCC), or physically devitalized cartilage particles (DVC). The chemical decellularization process removed the vast majority of DNA and about half of the glycosaminoglycans (GAG) within the matrix, but had no significant effect on the amount of hydroxyproline. Most notably, the DCC group significantly outperformed TGF-β in chondroinduction of rBMSCs, with collagen II gene expression an order of magnitude or more higher. While DVC did not exhibit a chondrogenic response to the extent that DCC did, DVC had a greater down regulation of collagen I, collagen X and Runx2. A new protocol has been introduced for cartilage devitalization and decellularization in the current study, with evidence of chondroinductivity. Such bioactivity along with providing the ‘raw material’ building blocks of regenerating cartilage may suggest a promising role for DCC in biomaterials that rely on recruiting endogenous cell recruitment and differentiation for cartilage regeneration.
PMCID: PMC4428768  PMID: 25965981
6.  Mapping Glycosaminoglycan–Hydroxyapatite Colloidal Gels as Potential Tissue Defect Fillers 
Langmuir  2014;30(12):3528-3537.
Malleable biomaterials such as Herschel–Bulkley (H–B) fluids possess shear responsive rheological properties and are capable of self-assembly and viscoelastic recovery following mechanical disruption (e.g., surgical placement via injection or spreading). This study demonstrated that the addition of moderate molecular weight glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) (Mw = 15–30 kDa) and hyaluronic acid (HA) (Mw = 20–41 kDa) can be used to modify several rheological properties including consistency index (K), flow-behavior index (n), and yield stress (τy) of submicrometer hydroxyapatite (HAP) (Davg ≤ 200 nm) colloidal gels. GAG–HAP colloidal mixtures exhibited substantial polymer–particle synergism, likely due to “bridging” flocculation, which led to a synergistic increase in consistency index (KGAG-HAP ≥ KGAG + KHAP) without compromising shear-thinning behavior (n < 1) of the gel. In addition, GAG–HAP colloids containing high concentrations of HAP (60–80% w/v) exhibited substantial yield stress (τy ≥ 100 Pa) and viscoelastic recovery properties (G′recovery ≥ 64%). While rheological differences were observed between CS–HAP and HA–HAP colloidal gels, both CS and HA represent feasible options for future studies involving bone defect filling. Overall, this study identified mixture regions where rheological properties in CS–HAP and HA–HAP colloidal gels aligned with desired properties to facilitate surgical placement in non-load-bearing tissue-filling applications such as calvarial defects.
PMCID: PMC3974614  PMID: 24606047
7.  Microsphere-Based Scaffolds Carrying Opposing Gradients of Chondroitin Sulfate and Tricalcium Phosphate 
Extracellular matrix (ECM) components, such as chondroitin sulfate (CS) and tricalcium phosphate, serve as raw materials, and thus spatial patterning of these raw materials may be leveraged to mimic the smooth transition of physical, chemical, and mechanical properties at the bone-cartilage interface. We hypothesized that encapsulation of opposing gradients of these raw materials in high molecular weight poly(d,l-lactic-co-glycolic acid) (PLGA) microsphere-based scaffolds would enhance differentiation of rat bone marrow–derived stromal cells. The raw material encapsulation altered the microstructure of the microspheres and also influenced the cellular morphology that depended on the type of material encapsulated. Moreover, the mechanical properties of the raw material encapsulating microsphere-based scaffolds initially relied on the composition of the scaffolds and later on were primarily governed by the degradation of the polymer phase and newly synthesized ECM by the seeded cells. Furthermore, raw materials had a mitogenic effect on the seeded cells and led to increased glycosaminoglycan (GAG), collagen, and calcium content. Interestingly, the initial effects of raw material encapsulation on a per-cell basis might have been overshadowed by medium-regulated environment that appeared to favor osteogenesis. However, it is to be noted that in vivo, differentiation of the cells would be governed by the surrounding native environment. Thus, the results of this study demonstrated the potential of the raw materials in facilitating neo-tissue synthesis in microsphere-based scaffolds and perhaps in combination with bioactive signals, these raw materials may be able to achieve intricate cell differentiation profiles required for regenerating the osteochondral interface.
PMCID: PMC4486839  PMID: 26191526
raw materials; chondroitin sulfate; tricalcium phosphate; gradient; microsphere-based scaffolds
8.  Dynamic Measurements of Membrane Insertion Potential of Synthetic Cell Penetrating Peptides 
Cell penetrating peptides (CPPs) have been established as excellent candidates for mediating drug delivery into cells. When designing synthetic CPPs for drug delivery applications, it is important to understand their ability to penetrate the cell membrane. In this paper, anionic or zwitterionic phospholipid monolayers at the air-water interface are used as model cell membranes to monitor the membrane insertion potential of synthetic CPPs. The insertion potential of CPPs having different cationic and hydrophobic amino acids were recorded using a Langmuir monolayer approach that records peptide adsorption to model membranes. Fluorescence microscopy was used to visualize alterations in phospholipid packing due to peptide insertion. All CPPs had the highest penetration potential in the presence of anionic phospholipids. In addition, two of three amphiphilic CPPs inserted into zwitterionic phospholipids, but none of the hydrophilic CPPs did. All the CPPs studied induced disruptions in phospholipid packing and domain morphology, which were most pronounced for amphiphilic CPPs. Overall, small changes to amino acids and peptide sequences resulted in dramatically different insertion potentials and membrane reorganization. Designers of synthetic CPPs for efficient intracellular drug delivery should consider small nuances in CPP electrostatic and hydrophobic properties.
PMCID: PMC3918496  PMID: 24294979
Cell penetrating peptides; Langmuir; Surface pressure; Amphiphilic; Hydrophilic; Phospholipid monolayers; POPG; POPC; DPPC
9.  Noncovalently associated -penetrating peptides for gene delivery applications 
Therapeutic delivery  2013;4(6):741-757.
The use of various cell-penetrating peptides (CPPs) to deliver genetic material for gene therapy applications has been a topic of interest for more than 20 years. The delivery of genetic material by using CPPs can be divided into two categories: covalently bound and electrostatically bound. Complexity of the synthesis procedure can be a significant barrier to translation when using a strategy requiring covalent binding of CPPs. In contrast, electrostatically complexing CPPs with genetic material or with a viral vector is relatively simple and has been demonstrated to improve gene delivery in both in vitro and in vivo studies. This review highlights gene therapy applications of complexes formed noncovalently between CPPs and genetic material or viruses.
PMCID: PMC4207642  PMID: 23738670
10.  Polyarginine Molecular Weight Determines Transfection Efficiency of Calcium Condensed Complexes 
Molecular pharmaceutics  2013;10(5):1940-1948.
Cell penetrating peptides (CPPs) have been extensively studied in polyelectrolyte complexes as a means to enhance the transfection efficiency of plasmid DNA (pDNA). Increasing the molecular weight of CPPs often enhances gene expression, but poses a risk of increased cytotoxicity and immunogenicity compared to low molecular weight CCPs. Conversely, low molecular weight CPPs typically have low transfection efficiency due to large complex size. Complexes made using low molecular weight CPPs were found to be condensed to a small size by adding calcium. In this study, complexes of low molecular weight polyarginine and pDNA were condensed with calcium. These complexes showed high transfection efficiency and low cytotoxicity in A549 carcinomic human alveolar basal epithelial cells. The relationship between transfection efficiency and polyarginine size (5, 7, 9 or 11 amino acids), polyarginine/pDNA charge ratios, and calcium concentrations were studied. Polyarginine 7 was significantly more effective than other polyarginines under most formulation conditions suggesting a link between cell penetration ability and transfection efficiency.
PMCID: PMC4207646  PMID: 23534410
plasmid DNA; polyarginine; cell-penetrating peptides; A549 cells; non-viral gene delivery; calcium chloride; transfection
11.  Calcium condensation of DNA complexed with cell-penetrating peptides offers efficient, noncytotoxic gene delivery 
Journal of pharmaceutical sciences  2010;100(5):1637-1642.
Drug delivery strategies using cell penetrating peptides (CPPs) have been widely explored to improve the intracellular delivery of a large number of cargo molecules. Electrostatic complexation of pDNA using CPPs has been less explored due to the relatively large complexes formed and the low levels of gene expression achieved when using these low molecular weight polycations as DNA condensing agents. Here, condensing nascent CPP polyplexes using CaCl2 produced small and stable nanoparticles leading to gene expression levels higher than observed for control PEI gene vectors. This simple formulation approach showed negligible cytotoxicity in A549 lung epithelial cells and maintained particle size and transfection efficiency even in the presence of serum.
PMCID: PMC4207659  PMID: 21374602
Gene Delivery; Plasmid DNA; Cell-penetrating peptides; A549 cells
12.  Effect of different sintering methods on bioactivity and release of proteins from PLGA microspheres 
Macromolecule release from poly(d,l-lactide-co-glycolide) (PLGA) microspheres has been well-characterized, and is a popular approach for delivering bioactive signals from tissue-engineered scaffolds. However, the effect of some processing solvents, sterilization, and mineral incorporation (when used in concert) on long-term release and bioactivity has seldom been addressed. Understanding these effects is of significant importance for microsphere-based scaffolds, given that these scaffolds are becoming increasingly more popular, yet growth factor activity following sintering and/or sterilization is heretofore unknown. The current study evaluated the 6-week release of transforming growth factor (TGF)-β3 and bone morphogenetic protein (BMP)-2 from PLGA and PLGA/hydroxyapatite (HAp) microspheres following exposure to ethanol (EtOH), dense phase carbon dioxide (CO2), or ethylene oxide (EtO). EtO was chosen based on its common use in scaffold sterilization, whereas EtOH and CO2 were chosen given their importance in sintering microspheres together to create scaffolds. Release supernatants were then used in an accelerated cell stimulation study with human bone marrow stromal cells (hBMSCs) with monitoring of gene expression for major chondrogenic and osteogenic markers. Results indicated that in microspheres without HAp, EtOH exposure led to the greatest amount of delivery, whilst those treated with CO2 delivered the least growth factor. In contrast, formulations with HAp released almost half as much protein, regardless of EtOH or CO2 exposure. Notably, EtO exposure was not found to significantly affect the amount of protein released. Cell stimulation studies demonstrated that eluted protein samples performed similarly to positive controls in PLGA-only formulations, and ambiguously in PLGA/HAp composites. In conclusion, the use of EtOH, subcritical CO2, and EtO in microsphere-based scaffolds may have only slight adverse effects, and possibly even desirable effects in some cases, on protein availability and bioactivity.
PMCID: PMC3752427  PMID: 23910352
PLGA; Microspheres; Growth Factors; Ethanol; CO2; Hydroxyapatite
13.  Osteochondral Interface Tissue Engineering Using Macroscopic Gradients of Bioactive Signals 
Annals of biomedical engineering  2010;38(6):2167-2182.
Continuous gradients exist at osteochondral interfaces, which may be engineered by applying spatially patterned gradients of biological cues. In the present study, a protein-loaded microsphere-based scaffold fabrication strategy was applied to achieve spatially and temporally controlled delivery of bioactive signals in three-dimensional (3D) tissue engineering scaffolds. Bone morphogenetic protein-2 and transforming growth factor-β1-loaded poly(d,llactic- co-glycolic acid) microspheres were utilized with a gradient scaffold fabrication technology to produce microsphere-based scaffolds containing opposing gradients of these signals. Constructs were then seeded with human bone marrow stromal cells (hBMSCs) or human umbilical cord mesenchymal stromal cells (hUCMSCs), and osteochondral tissue regeneration was assessed in gradient scaffolds and compared to multiple control groups. Following a 6-week cell culture, the gradient scaffolds produced regionalized extracellular matrix, and outperformed the blank control scaffolds in cell number, glycosaminoglycan production, collagen content, alkaline phosphatase activity, and in some instances, gene expression of major osteogenic and chondrogenic markers. These results suggest that engineered signal gradients may be beneficial for osteochondral tissue engineering.
PMCID: PMC3773241  PMID: 20379780
Osteochondral; Interface; Gradient; Microsphere; Umbilical cord stem cells; PLGA; BMP-2; TGF-β1
14.  Emerging Techniques in Stratified Designs and Continuous Gradients for Tissue Engineering of Interfaces 
Annals of biomedical engineering  2010;38(6):2121-2141.
Interfacial tissue engineering is an emerging branch of regenerative medicine, where engineers are faced with developing methods for the repair of one or many functional tissue systems simultaneously. Early and recent solutions for complex tissue formation have utilized stratified designs, where scaffold formulations are segregated into two or more layers, with discrete changes in physical or chemical properties, mimicking a corresponding number of interfacing tissue types. This method has brought forth promising results, along with a myriad of regenerative techniques. The latest designs, however, are employing “continuous gradients” in properties, where there is no discrete segregation between scaffold layers. This review compares the methods and applications of recent stratified approaches to emerging continuously graded methods.
PMCID: PMC3729916  PMID: 20411333
Gradient; Stratified; Interface; Tissue engineering; Osteochondral
15.  Osteogenic Differentiation of Human Bone Marrow Stromal Cells in Hydroxyapatite-Loaded Microsphere-Based Scaffolds 
Tissue Engineering. Part A  2011;18(7-8):757-767.
Calcium-based minerals have consistently been shown to stimulate osteoblastic behavior in vitro and in vivo. Thus, use of such minerals in biomaterial applications has become an effective method to enhance bone tissue engineered constructs. In the present study, for the first time, human bone marrow stromal cells (hBMSC) were osteogenically differentiated on scaffolds consisting only of hydroxyapatite (HAp)-loaded poly(d,l-lactic acid-co-glycolic acid) (PLGA) microspheres of high monodispersity. Scaffold formulations included 0, 5, 10, and 20 wt% Hap, and the hBMSC were cultured for 6 weeks. Results demonstrated suppression of some osteogenic genes during differentiation in the HAp group, but higher end-point glycosaminoglycan and collagen content in 10% and 20% HAp samples, as evidenced by biochemical tests, histology, and immunohistochemistry. After 6 weeks of culture, constructs with 0% and 5% HAp had average compressive moduli of 0.7±0.2 and 1.5±0.9 kPa, respectively, whereas constructs with 10% and 20% HAp had higher average moduli of 17.6±4.6 and 18.9±8.1 kPa, respectively. The results of this study indicate that HAp inclusion in microsphere-based scaffolds could be implemented as a physical gradient in combination with bioactive signal gradients seen in previous iterations of these microsphere-based scaffolds to enhance osteoconduction and mechanical integrity of a healing site.
PMCID: PMC3313610  PMID: 21992088
To date, most interfacial tissue engineering approaches have utilized stratified designs, in which there are two or more discrete layers comprising the interface. Continuously-graded interfacial designs, where there is no discrete transition from one tissue type to another, are gaining attention as an alternative to stratified designs. Given that osteochondral regeneration holds the potential to enhance cartilage regeneration by leveraging the healing capacity of the underlying bone, we endeavored to introduce a continuously graded approach to osteochondral regeneration. The purpose of this study was thus to evaluate the performance of a novel gradient-based scaffolding approach to regenerate osteochondral defects in the New Zealand White rabbit femoral condyle. Bioactive plugs were constructed from poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres with a continuous gradient transition between cartilage-promoting and bone-promoting growth factors. At six and 12 weeks of healing, results suggested that the implants provided support for the neo-synthesized tissue, and the gradient in bioactive signaling may have been beneficial for bone and cartilage regeneration compared to the blank control implant, as evidenced by histology. In addition, the effects of pre-seeding gradient scaffolds with umbilical cord mesenchymal stromal cells (UCMSCs) from the Wharton’s jelly of New Zealand White rabbits were evaluated. Results indicated that there may be regenerative benefits to pre-localizing UCMSCs within scaffold interiors. The inclusion of bioactive factors in a gradient-based scaffolding design is a promising new treatment strategy for defect repair in the femoral condyle.
PMCID: PMC3222786  PMID: 22009693
Osteochondral; Interface; Gradient; Microsphere; Umbilical Cord Stem Cells; PLGA; BMP-2; TGF-β1
Tissue engineering solutions focused on the temporomandibular joint (TMJ) have expanded in number and variety over the past decade to address the treatment of TMJ disorders. The existing literature on approaches for healing small defects in the TMJ condylar cartilage and subchondral bone, however, is sparse. The purpose of this study was thus to evaluate the performance of a novel gradient-based scaffolding approach to regenerate osteochondral defects in the rabbit mandibular condyle.
Miniature bioactive plugs for regeneration of small mandibular condylar defects in New Zealand White rabbits were fabricated. The plugs were constructed from poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres with a gradient transition between cartilage-promoting and bone-promoting growth factors.
At six weeks of healing, results suggested that the implants provided support for the neo-synthesized tissue as evidenced by histology and 9.4T magnetic resonance imaging.
The inclusion of bioactive factors in a gradient-based scaffolding design is a promising new treatment strategy for focal defect repair in the TMJ.
PMCID: PMC3101307  PMID: 21470747
TMJ; Osteochondral; Interface; Gradient; Microsphere; PLGA; BMP-2; TGF-β1
18.  Pulmonary delivery of cisplatin-hyaluronan conjugates via endotracheal instillation for the treatment of lung cancer 
International journal of pharmaceutics  2010;392(1-2):156-163.
Cisplatin (CDDP) intravenous treatments suffer several dose-limiting toxicity issues. Hyaluronan (HA), a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic system. An alteration in input rate and administration route through pulmonary delivery of hyaluronan-cisplatin conjugate (HA-Pt) may increase local lung CDDP concentrations and decrease systemic toxicity.
Sprague-Dawley rats were split into four groups: i.v. CDDP (3.5 mg/kg), i.v. HA-Pt conjugate (3.5 mg/kg equivalent CDDP), lung instillation CDDP and lung instillation HA-Pt conjugate. Total platinum level in the lungs of the HA-Pt lung instillation group was 5.7-fold and 1.2-fold higher than the CDDP intravenous group at 24 h and 96 h, respectively. A 1.1-fold increase of Pt accumulation in lung draining nodes for the HA-Pt lung instillation group was achieved at 24 h relative to the CDDP i.v. group. In the brain and kidneys, the CDDP i.v. group had higher tissue/plasma ratios compared to the HA-Pt lung instillation group. Augmented tissue distribution from CDDP i.v. could translate into enhanced tissue toxicity compared to the altered input rate and distribution of the intrapulmonary nanoformulation.
In conclusion, a local pulmonary CDDP delivery system was developed with increased platinum concentration in the lungs and draining nodes compared to i.v. therapy.
PMCID: PMC2873163  PMID: 20363303
cisplatin; hyaluronan; pharmacokinetics; pulmonary delivery; lung chemotherapeutics
19.  Nanoparticles for biomedical imaging 
Expert opinion on drug delivery  2009;6(11):1175-1194.
Synthetic nanoparticles are emerging as versatile tools in biomedical applications, particularly in the area of biomedical imaging. Nanoparticles 1 – 100 nm in diameter have dimensions comparable to biological functional units. Diverse surface chemistries, unique magnetic properties, tunable absorption and emission properties, and recent advances in the synthesis and engineering of various nanoparticles suggest their potential as probes for early detection of diseases such as cancer. Surface functionalization has expanded further the potential of nanoparticles as probes for molecular imaging.
To summarize emerging research of nanoparticles for biomedical imaging with increased selectivity and reduced nonspecific uptake with increased spatial resolution containing stabilizers conjugated with targeting ligands.
This review summarizes recent technological advances in the synthesis of various nanoparticle probes, and surveys methods to improve the targeting of nanoparticles for their application in biomedical imaging.
Structural design of nanomaterials for biomedical imaging continues to expand and diversify. Synthetic methods have aimed to control the size and surface characteristics of nanoparticles to control distribution, half-life and elimination. Although molecular imaging applications using nanoparticles are advancing into clinical applications, challenges such as storage stability and long-term toxicology should continue to be addressed.
PMCID: PMC3097035  PMID: 19743894
biomedical imaging; molecular imaging; nanoparticle synthesis; surface modification; targeting
20.  Effects of nanomaterial physicochemical properties on in vivo toxicity 
Advanced drug delivery reviews  2009;61(6):457-466.
It is well recognized that physical and chemical properties of materials can alter dramatically at nanoscopic scale, and the growing use of nanotechnologies requires careful assessment of unexpected toxicities and biological interactions. However, most in vivo toxicity concerns focus primarily on pulmonary, oral, and dermal exposure to ultrafine particles. As nanomaterials expand as therapeutics and as diagnostic tools, parenteral administration of engineered nanomaterials should also be recognized as a critical aspect for toxicity consideration. Due to the complex nature of nanomaterials, conflicting studies have led to different views of their safety. Here, the physicochemical properties of four representative nanomaterials (dendrimers, carbon nanotubes, quantum dots, and gold nanoparticles) as it relates to their toxicity after systemic exposure is discussed.
PMCID: PMC2743376  PMID: 19386275
nanomaterial; toxicity; in vivo; dendrimer; carbon nanotube; quantum dot; gold nanoparticle; analysis
21.  Pure Insulin Nanoparticle Agglomerates for Pulmonary Delivery 
Diabetes is a set of diseases characterized by defects in insulin utilization, either through autoimmune destruction of insulin-producing cells (Type I) or insulin resistance (Type II). Treatment options can include regular injections of insulin, which can be painful and inconvenient, often leading to low patient compliance. To overcome this problem, novel formulations of insulin are being investigated, such as inhaled aerosols. Sufficient deposition of powder in the peripheral lung to maximize systemic absorption requires precise control over particle size and density, with particles between 1 and 5 μm in aerodynamic diameter being within the respirable range. Insulin nanoparticles were produced by titrating insulin dissolved at low pH up to the pI of the native protein, and were then further processed into microparticles using solvent displacement. Particle size, crystallinity, dissolution properties, structural stability, and bulk powder density were characterized. We have demonstrated that pure drug insulin microparticles can be produced from nanosuspensions with minimal processing steps without excipients, and with suitable properties for deposition in the peripheral lung.
PMCID: PMC2649680  PMID: 18959432
Insulin; Diabetes; Pulmonary Medicine; Crystallinity

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