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1.  Macrophage Phenotype as a Predictor of Constructive Remodeling following the Implantation of Biologically Derived Surgical Mesh Materials 
Acta biomaterialia  2011;8(3):978-987.
Macrophages have been classified as having plastic phenotypes which exist within a spectrum between M1 (classically activated; pro-inflammatory) and M2 (alternatively activated; regulatory, homeostatic). To date, the effects of polarization towards a predominantly M1 or M2 phenotype have been studied largely in the context of response to pathogen or cancer. Recently, M1 and M2 macrophages have been shown to play distinct roles in tissue remodeling following injury. In the present study, the M1/M2 paradigm was utilized to examine the role of macrophages in the remodeling process following implantation of 14 biologically derived surgical mesh materials in the rat abdominal wall. In situ polarization of macrophages responding to the materials was examined and correlated to a quantitative measure of the observed tissue remodeling response to determine whether macrophage polarization is an accurate predictor of the ability of a biologic scaffold to promote constructive tissue remodeling. Additionally the ability of M1 and M2 macrophages to differentially recruit progenitor-like cells in vitro, which are commonly observed to participate in the remodeling of those ECM scaffolds which have a positive clinical outcome, was examined as a possible mechanism underlying the differences in the observed remodeling responses. The results of the present study show that there is a strong correlation between the early macrophage response to implanted materials and the outcome of tissue remodeling. Increased numbers of M2 macrophages and higher ratios of M2:M1 macrophages within the site of remodeling at 14 days were associated with more positive remodeling outcomes (r2=0.525–0.686, p<0.05). Further, the results of the present study suggest that the constructive remodeling outcome may be due to the recruitment and survival of different cell populations to the sites of remodeling associated with materials that elicit an M1 versus M2 response. Both M2 and M0 macrophage conditioned medias were shown to have higher chemotactic activities than media conditioned by M1 macrophages (p<0.05). A more thorough understanding of these issues will logically influence the design of next generation biomaterials and the development of regenerative medicine strategies for the formation of functional host tissues.
doi:10.1016/j.actbio.2011.11.031
PMCID: PMC4325370  PMID: 22166681
2.  [No title available] 
PMCID: PMC3889126  PMID: 24200714
3.  [No title available] 
PMCID: PMC3956052  PMID: 24161384
4.  [No title available] 
PMCID: PMC4059047  PMID: 24211612
5.  Elastic modulus and collagen organization of the rabbit cornea: epithelium to endothelium 
Acta biomaterialia  2013;10(2):785-791.
The rabbit is commonly used to evaluate new corneal prosthetics and study corneal wound healing. Knowledge of the stiffness of the rabbit cornea would better inform design and fabrication of keratoprosthetics and substrates with relevant mechanical properties for in vitro investigations of corneal cellular behavior. This study determined the elastic modulus of the rabbit corneal epithelium, anterior basement membrane (ABM), anterior and posterior stroma, Descemet’s membrane (DM) and endothelium using atomic force microscopy (AFM). In addition, three-dimensional collagen fiber organization of the rabbit cornea was determined using nonlinear optical high-resolution macroscopy. Elastic modulus as determined by AFM for each corneal layer was: epithelium 0.57 ± 0.29 kPa (mean ± SD), ABM 4.5 ± 1.2 kPa, anterior stroma 1.1 ± 0.6 kPa, posterior stroma 0.38 ± 0.22 kPa, DM 11.7 ± 7.4 kPa, and endothelium 4.1 ± 1.7 kPa. Biophysical properties, including elastic modulus, are unique for each layer of the rabbit cornea and are dramatically softer in comparison to the corresponding regions of the human cornea. Collagen fiber organization is also dramatically different between the two species with markedly less intertwining observed in the rabbit versus human cornea. Given that substratum stiffness considerably alters corneal cell behavior, keratoprosthetics that incorporate mechanical properties simulating the native human cornea may not elicit optimal cellular performance in rabbit corneas that have dramatically different elastic moduli. These data will allow for the design of substrates that better mimic the biomechanical properties of the corneal cellular environment.
doi:10.1016/j.actbio.2013.09.025
PMCID: PMC4280096  PMID: 24084333
cornea; elastic modulus; AFM; nonlinear optical high-resolution macroscopy; rabbit
6.  Keratocyte behavior in three-dimensional photopolymerizable poly(ethylene glycol) hydrogels 
Acta biomaterialia  2008;4(5):1139-1147.
The goal of this study was to evaluate three-dimensional (3-D) poly(ethylene glycol) (PEG) hydrogels as a culture system for studying corneal keratocytes. Bovine keratocytes were subcultured in DMEM/F-12 containing 10% fetal bovine serum (FBS) through passage 5. Primary keratocytes (P0) and corneal fibroblasts from passages 1 (P1) and 3 (P3) were photoencapsulated at various cell concentrations in PEG hydrogels via brief exposure to light. Additional hydrogels contained adhesive YRGDS and nonadhesive YRDGS peptides. Hydrogel constructs were cultured in DMEM/F-12 with 10% FBS for 2 and 4 weeks. Cell viability was assessed by DNA quantification and vital staining. Biglycan, type I collagen, type III collagen, keratocan and lumican expression were determined by reverse transcriptase–polymerase chain reaction. Deposition of type I collagen, type III collagen and keratan sulfate (KS)-containing matrix components was visualized using confocal microscopy. Keratocytes in a monolayer lost their stellate morphology and keratocan expression, displayed elongated cell bodies, and up-regulated biglycan, type I collagen and type III collagen characteristic of corneal fibroblasts. Encapsulated keratocytes remained viable for 4 weeks with spherical morphologies. Hydrogels supported production of KS, type I collagen and type III collagen matrix components. PEG-based hydrogels can support keratocyte viability and matrix production. 3-D hydrogel culture can stabilize but not restore the keratocyte phenotype. This novel application of PEG hydrogels has potential use in the study of corneal keratocytes in a 3-D environment.
doi:10.1016/j.actbio.2008.05.007
PMCID: PMC4305385  PMID: 18567550
Keratocytes; Cornea; Scaffold; PEG; Tissue engineering
7.  Microtopographical effects of natural scaffolding on cardiomyocyte function and arrhythmogenesis 
Acta biomaterialia  2010;6(8):3029-3034.
A natural myocardial patch for heart regeneration derived from porcine urinary bladder matrix (UBM) was previously reported to outperform synthetic materials (Dacron and expanded polytetrafluoroethylene (ePTFE)) used in current surgical treatments. UBM, an extracellular matrix prepared from urinary bladder, has intricate three-dimensional architecture with two distinct sides: the luminal side with a smoother surface relief; and the abluminal side with a fine mesh of nano- and microfibers. This study tested the ability of this natural scaffold to support functional cardiomyocyte networks, and probed how the local microtopography and composition of the two sides affects cell function. Cardiomyocytes isolated from neonatal rats were seeded in vitro to form cardiac tissue onto luminal (L) or abluminal (Ab) UBM. Immunocytochemistry of contractile cardiac proteins demonstrated growth of cardiomyocyte networks with mature morphology on either side of UBM, but greater cell compactness was seen in L. Fluorescence-based imaging techniques were used to measure dynamic changes in intracellular calcium concentration upon electrical stimulation of L and Ab-grown cells. Functional differences in cardiac tissue grown on the two sides manifested themselves in faster calcium recovery (p < 0.04) and greater hysteresis (difference in response to increasing and decreasing pacing rates) for L vs Ab side (p < 0.03). These results suggest that surface differences may be leveraged to engineer the desired cardiomyocyte responses and highlight the potential of natural scaffolds for fostering heart repair.
doi:10.1016/j.actbio.2010.02.041
PMCID: PMC4299823  PMID: 20197129
Urinary bladder matrix; Scaffolding; Cardiomyocytes; Topography; Electrical stability
8.  In vivo performance of novel soybean/gelatin-based bioactive and injectable hydroxyapatite foams 
Acta Biomaterialia  2015;12:242-249.
Graphical abstract
Major limitations of calcium phosphate cements (CPCs) are their relatively slow degradation rate and the lack of macropores allowing the ingrowth of bone tissue. The development of self-setting cement foams has been proposed as a suitable strategy to overcome these limitations. In previous work we developed a gelatine-based hydroxyapatite foam (G-foam), which exhibited good injectability and cohesion, interconnected porosity and good biocompatibility in vitro. In the present study we evaluated the in vivo performance of the G-foam. Furthermore, we investigated whether enrichment of the foam with soybean extract (SG-foam) increased its bioactivity. G-foam, SG-foam and non-foamed CPC were implanted in a critical-size bone defect in the distal femoral condyle of New Zealand white rabbits. Bone formation and degradation of the materials were investigated after 4, 12 and 20 weeks using histological and biomechanical methods. The foams maintained their macroporosity after injection and setting in vivo. Compared to non-foamed CPC, cellular degradation of the foams was considerably increased and accompanied by new bone formation. The additional functionalization with soybean extract in the SG-foam slightly reduced the degradation rate and positively influenced bone formation in the defect. Furthermore, both foams exhibited excellent biocompatibility, implying that these novel materials may be promising for clinical application in non-loaded bone defects.
doi:10.1016/j.actbio.2014.10.034
PMCID: PMC4298359  PMID: 25448348
Calcium phosphate cement; Gelatine; Soybean; Bone regeneration; Rabbit model
9.  Role of non-canonical Wnt signaling in osteoblast maturation on microstructured titanium surfaces 
Acta biomaterialia  2011;7(6):2740-2750.
The Wnt signaling pathway inhibitor Dickkopf-2 (Dkk2) regulates osteoblast differentiation on microstructured titanium (Ti) surfaces, suggesting involvement of Wnt signaling in this process. To test this, human osteoblast-like MG63 cells were cultured on tissue culture polystyrene or Ti (smooth PT (Ra = 0.2 μm), sand-blasted and acid-etched SLA (Ra = 3.22 μm), modSLA (hydrophilic SLA)). Expression of Wnt pathway receptors, activators and inhibitors was measured by qPCR. Non-canonical pathway ligands, receptors and intracellular signaling molecules, as well as bone morphogenetic proteins BMP2 and BMP4, were upregulated on SLA and modSLA, whereas canonical pathway members were downregulated. To confirm that non-canonical signaling was involved, cells were cultured daily with exogenous Wnt3a (canonical pathway) or Wnt5a (non-canonical pathway). Alternatively, cells were cultured with antibodies to Wnt3a or Wnt5a to validate that Wnt proteins secreted by the cells were mediating cell responses to the surface. Wnt5a, but not Wnt3a, increased MG63 cell differentiation and BMP2 and BMP4 proteins, suggesting Wnt5a promotes osteogenic differentiation through production of BMPs. Effects of exogenous and endogenous Wnt5a were synergistic with surface microstructure, suggesting the response also depends on cell maturation state. These results indicate a major role for the non-canonical, calcium-dependent Wnt pathway in differentiation of osteoblasts on microstructured titanium surfaces during implant osseointegration.
doi:10.1016/j.actbio.2011.02.030
PMCID: PMC4287412  PMID: 21352958
Cell signaling; Titanium surface roughness; Osteoblast differentiation; Gene expression; Regulatory factors
10.  Swelling equilibrium of dentin adhesive polymers formed on the water-adhesive phase boundary: Experiments and micromechanical model 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.017.
During their application to the wet, oral environment, dentin adhesives can experience phase separation and composition change which can compromise the quality of the hybrid layer formed at the dentin-adhesive interface. The chemical composition of polymer phases formed in the hybrid layer can be represented using a ternary water-adhesive phase diagram. In this paper, these polymer phases have been characterized using a suite of mechanical tests and swelling experiments. The experimental results were evaluated using granular micromechanics based model that incorporates poro-mechanical effects and polymer-solvent thermodynamics. The variation of the model parameters and model-predicted polymer properties has been studied as a function of composition along the phase boundary. The resulting structure-property correlations provide insight into interactions occurring at the molecular level in the saturated polymer system. These correlations can be used for modeling the mechanical behavior of hybrid layer, and are expected to aid in the design and improvement of water-compatible dentin adhesive polymers.
doi:10.1016/j.actbio.2013.09.017
PMCID: PMC3843361  PMID: 24076070
dentin adhesive; phase diagram; absorption; swelling; micromechanics; crosslink density; elastic modulus
11.  Chronic inflammation in biomaterial induced periprosthetic osteolysis: NF-κB as a therapeutic target 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.034.
Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, MCP1, etc. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment, however, the timing, dose, and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.
doi:10.1016/j.actbio.2013.09.034
PMCID: PMC3849197  PMID: 24090989
Biomaterials; periprosthetic osteolysis; chronic inflammation; NF-κB
12.  Bioerodible System for Sequential Release of Multiple Drugs 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.031.
Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule.
doi:10.1016/j.actbio.2013.09.031
PMCID: PMC3850105  PMID: 24096151
multiple drug delivery; sequential drug release; zero-order release; cellulose acetate phthalate; Pluronic F-127
13.  Effects of clodronate and alendronate on osteoclast and osteoblast co-cultures on silk-hydroxyapatite films 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.028.
The goal of this study was to explore the effects of osteoporosis-related therapeutics on bone remodeling in vitro. A previously established bone-tissue mimetic system consisting of silk protein biomaterials in combination with hydroxyapatite and human cells was used for the study. Silk-hydroxyapatite films were pre-complexed with the non-nitrogenous bisphosphonate clodronate or the nitrogenous bisphosphonate alendronate and cultured with THP-1 human acute monocytic leukemia cell line-derived osteoclasts, human mesenchymal stem cell derived-osteoblasts, or a direct co-culture of the two cell types. Metabolic activity, calcium deposition, and alkaline phosphatase activity were assessed over 12 weeks, and reconstructed remodeled biomaterial surfaces were also evaluated for quantitative morphological changes. Increased metabolic activity and increased roughness were found on the clodronate-complexed biomaterial substrates remodeled by osteoblasts and co-cultures of osteoblasts with osteoclasts, even at doses high enough to cause a 90 percent decrease in osteoclast metabolic activity. Films complexed with low doses of alendronate resulted in increased metabolic activity and calcium deposition by osteoblasts, while higher doses were similarly toxic among osteoclasts, osteoblasts, and cocultures. These results point to the utility of these well-defined bone-mimetic in vitro cultures as useful screens for therapeutics for bone-related diseases, particularly with the ability to conduct studies for extended duration (here for 12 weeks) and with pre-complexed drugs to mimic conditions found in vivo.
doi:10.1016/j.actbio.2013.09.028
PMCID: PMC3863115  PMID: 24096150
osteoporosis; co-culture; bisphosphonates; silk
14.  Dual-crosslinked oxidized, methacrylated alginate/PEG hydrogels for bioadhesive applications 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.004.
A degradable, cytocompatible bioadhesive can facilitate surgical procedures and minimize patient pain and postsurgical complications. In this study, a bioadhesive hydrogel system based on oxidized, methacrylated alginate/8-arm poly(ethylene glycol) amine (OMA/PEG) has been developed, and the bioadhesive characteristics of the crosslinked OMA/PEG hydrogels are evaluated. Here, we demonstrate that the swelling behavior, degradation profiles, and storage moduli of crosslinked OMA/PEG hydrogels are tunable by varying the degree of alginate oxidation. The crosslinked OMA/PEG hydrogels exhibit cytocompatibility when cultured with human bone marrow-derived mesenchymal stem cells. In addition, the adhesion strength of these hydrogels, controllable by varying the alginate oxidation level and measured using a porcine skin model, is superior to commercially available fibrin glue. This OMA/PEG hydrogel system with controllable biodegradation and mechanical properties and adhesion strength may be a promising bioadhesive for clinical use in biomedical applications, such as drug delivery, wound closure and healing, biomedical device implantation, and tissue engineering.
doi:10.1016/j.actbio.2013.09.004
PMCID: PMC3840035  PMID: 24035886
bioadhesive; alginate; PEG; biodegradation; adhesion
15.  Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.037.
A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development and studies suggest it plays an important role in regulating myocyte proliferation. Here, we studied the effects of fetal, neonatal, and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro. At 24 hr, overall cell attachment was lowest on fetal ECM; however ∼80% of the cells were cardiomyocytes while many non-myocytes attached to older ECM and poly-L-lysine controls. After 5 days, the cardiomyocyte population remained highest on fetal ECM, with a 4-fold increase in number. Significantly more cardiomyocytes stained positively for the mitotic marker phospho-histone H3 on fetal ECM compared to other substrates at 5 days, suggesting that proliferation may be a major mechanism of cardiomyocyte expansion on young ECM. Further study of the beneficial properties of early developmental aged cardiac ECM could advance the design of novel biomaterials aimed at promoting cardiac regeneration.
doi:10.1016/j.actbio.2013.08.037
PMCID: PMC3840040  PMID: 24012606
cardiac tissue engineering; cardiomyocyte; proliferation; extracellular matrix
16.  Visible light cured thiol-vinyl hydrogels with tunable degradation for 3D cell culture 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.044.
We report here a synthetically simple yet highly tunable and diverse visible light mediated thiol-vinyl gelation system for fabricating cell-instructive hydrogels. Gelation was achieved via a mixed-mode step-and-chain-growth photopolymerization using functionalized 4-arm poly(ethylene glycol) as backbone macromer, eosin-Y as photosensitizer, and di-thiol containing molecule as dual purpose co-initiator/cross-linker. N-vinylpyrrolidone (NVP) was used to accelerate gelation kinetics and to adjust the stiffness of the hydrogels. Visible light (wavelength: 400–700nm) was used to initiate rapid gelation (gel points: ~20 seconds) that reached completion within a few minutes. The major differences between current thiol-vinyl gelation and prior visible light mediated photopolymerization are that: (1) the co-initiator triethanolamine (TEOA) used in the previous systems was replaced with multifunctional thiols and (2) mixed-mode polymerized gels contain less network heterogeneity. The gelation kinetics and gel properties at the same PEG macromer concentration could be tuned by changing the identity of vinyl groups and di-thiol cross-linkers, as well as concentration of cross-linker and NVP. Specifically, acrylate-modified PEG afforded the fastest gelation rate, followed by acrylamide and methacrylate-functionalized PEG. Increasing NVP concentration also accelerated gelation and led to a higher network cross-linking density. Further, increasing di-thiol peptide concentration in the gel formulation increased hydrogel swelling and decreased gel stiffness. Due to the formation of thiol-ether-ester bonds following thiol-acrylate reaction, the gels degraded hydrolytically following a pseudo first order degradation kinetics. Degradation rate was controlled by adjusting thiol or NVP content in the polymer precursor solution. The cytocompatibility and utility of this hydrogel system were evaluated using in situ encapsulation of human mesenchymal stem cells (hMSC). Encapsulated hMSCs remained alive (>90%) throughout the duration of the study and the cells were differentiated down osteogenic lineage with varying degrees by controlling the rate and mode of gel degradation.
doi:10.1016/j.actbio.2013.08.044
PMCID: PMC3840055  PMID: 24021231
Visible light; photopolymerization; thiol-ene; hydrogels; mesenchymal stem cells
17.  Degradation in the Dentin-Composite Interface Subjected to Multi-Species Biofilm Challenges 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.034.
Oral biofilms can degrade the components in dental resin-based composite restorations, thus compromising marginal integrity and leading to secondary caries. In this study, we investigated the mechanical integrity of the dentin-composite interface challenged with multi-species oral biofilms. While most studies used single-species biofilms, we used a more realistic, diverse biofilm model produced directly from plaques collected from donors with a history of early childhood caries. Dentin–composite disks were made using bovine incisor roots filled with Z100™ or Filtek™ LS (3M ESPE). The disks were incubated for 72hr in paired CDC biofilm reactors, using a previously published protocol. One reactor was pulsed with sucrose, and the other was not. A sterile saliva-only control group was run with sucrose pulsing. The disks were fractured under diametral compression to evaluate their interfacial bond strength. Surface deformation of the disks was mapped using digital image correlation (DIC) to ascertain fracture origin. Fracture surfaces were examined using SEM/EDS to assess demineralization and interfacial degradation. Dentin demineralization was greater under sucrose-pulsed biofilms, as the pH dropped below 5.5 during pulsing, with LS and Z100 specimens suffering similar degrees of surface mineral loss. Biofilm growth with sucrose pulsing also caused preferential degradation of the composite-dentin interface, depending on the composite/adhesive system used. Specifically, Z100 specimens showed greater bond strength reduction and more frequent cohesive failure in the adhesive layer. This was attributed to the inferior dentin coverage by Z100 adhesive which possibly led to a higher level of chemical and enzymatic degradation. The results suggested that factors other than dentin demineralization were also responsible for interfacial degradation. We have thus developed a clinically relevant in vitro biofilm model which would allow us to effectively assess the degradation of the dentin-composite interface subjected to multi-species biofilm challenge.
doi:10.1016/j.actbio.2013.08.034
PMCID: PMC3840069  PMID: 24008178
multi-species biofilm; dental restoration; resin composite; degradation; bond strength; interface
18.  Effects of Crosslinking on the Mechanical Properties Drug Release, and Cytocompatibility of Protein Polymers 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.029.
Recombinant elastin-like protein polymers are increasingly being investigated as component materials of a variety of implantable medical devices. This is chiefly a result of their favorable biological properties and the ability to tailor their physical and mechanical properties. In this report, we explore the potential of modulating the water content, mechanical properties, and drug release profiles of protein films through the selection of different crosslinking schemes and processing strategies. We find that the selection of crosslinking scheme and processing strategy has a significant influence on all aspects of protein polymer films. Significantly, utilization of a confined, fixed volume, as well as vapor phase crosslinking strategies decreased protein polymer equilibrium water content. Specifically, as compared to uncrosslinked protein gels, water content was reduced for genipin (15.5%), glutaraldehyde (GTA) (24.5%), GTA vapor crosslinking (31.6%), disulfide (SS) (18.2%), and SS vapor crosslinking (25.5%) (p <0.05). Distinct crosslinking strategies modulated protein polymer stiffness, strain at failure, and ultimate tensile strength (UTS). In all cases, vapor phase crosslinking produced the stiffest films with the highest UTS. Moreover, both confined, fixed volume and vapor phase approaches influenced drug delivery rates; with decreased initial drug burst and release rates as compared to solution phase crosslinking. Tailored crosslinking strategies provide an important option for modulating the physical, mechanical, and drug delivery properties of protein polymers.
doi:10.1016/j.actbio.2013.08.029
PMCID: PMC3840084  PMID: 23993944
Protein polymer; crosslinking; mechanical properties; drug release
19.  Calcium phosphate deposition rate, structure and osteoconductivity on electrospun poly(l-lactic acid) matrix using electrodeposition or simulated body fluid incubation 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.041.
Mineralized nanofibrous scaffolds have been proposed as promising scaffolds for bone regeneration due to their ability to mimic both nanoscale architecture and chemical composition of natural bone extracellular matrix (ECM). In this study, a novel electrodeposition method was compared with an extensively explored simulated body fluid (SBF) incubation method in terms of the deposition rate, chemical composition, and morphology of calcium phosphate formed on electrospun fibrous thin matrices with a fiber diameter in the range from about 200 nm to about 1400 nm prepared using 6, 8, 10 and 12 wt% poly(l-lactic acid) (PLLA) solutions in a mixture of dichloromethane and acetone (2:1 in volume). The effects of the surface modification using the two mineralization techniques on osteoblastic cell (MC3T3-E1) proliferation and differentiation were also examined. It was found that electrodeposition was two to three orders of magnitude faster than the SBF method in mineralizing the fibrous matrices, reducing the mineralization time from about two weeks to an hour to achieve the same amounts of mineralization. The mineralization rate also varied with the fiber diameter but in opposite directions between the two mineralization methods. As a general trend, the increase of fiber diameter resulted in a faster mineralization rate for the electrodeposition method but a slower mineralization rate for the SBF incubation method. Using the electrodeposition method, one can control the chemical composition and morphology of the calcium phosphate by varying the electric deposition potential and electrolyte temperature to tune the mixture of dicalcium phosphate dihydrate (DCPD) and hydroxy apatite (HAp). Using the SBF method, one can only obtain a low crystallinity HAp. The mineralized electrospun PLLA fibrous matrices from either method similarly facilitate the proliferation and osteogenic differentiation of preosteoblastic MC3T3-E1 cells as compared to neat PLLA matrices. Therefore, the electrodeposition method can be utilized as a fast and versatile technique to fabricate mineralized nanofibrous scaffolds for bone tissue engineering.
doi:10.1016/j.actbio.2013.08.041
PMCID: PMC3840094  PMID: 24012605
Electrodeposition; SBF incubation; Calcium phosphate; Nanofiber; Bone tissue engineering
20.  The Effect of Detergents on the Basement Membrane Complex of a Biologic Scaffold Material 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.09.006.
The basement membrane complex (BMC) is a critical component of the extracellular matrix (ECM) that supports and facilitates the growth of cells. This study investigates four detergents commonly used in the process of tissue decellularization and their effect upon the BMC. The BMC of porcine urinary bladder was subjected to either 3% Triton-X 100, 8 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 4% sodium deoxycholate, or 1% sodium dodecyl sulfate (SDS) for 24 hours. The BMC structure for each treatment group was assessed by immunolabeling, scanning electron microscopy (SEM), and second harmonic generation (SHG) imaging of the fiber network. The composition was assessed by quantification of dsDNA, glycosaminoglycans (GAGs), and collagen content. Results showed that collagen fibers within samples treated with 1% SDS and 8 mM CHAPS were denatured and the ECM contained less GAGs compared to samples treated with 3% Triton X-100 or 4% sodium deoxycholate. Human microvascular endothelial cells (HMECs) were seeded onto each BMC and cultured for 7 days. Cell-ECM interactions were investigated by immunolabeling for integrin β-1, SEM imaging, and semi-quantitative assessment of cellular infiltration, phenotype, and confluence. HMECs cultured on a BMC treated with 3% Triton X-100 were more confluent and had a normal phenotype compared to HMECs cultured on a BMC treated with 4% sodium deoxycholate, 8 mM CHAPS, and 1% SDS. Both 8 mM CHAPS and 1% SDS damaged the BMC to the extent that seeded HMECs were able to infiltrate the damaged sub-basement membrane tissue, showed decreased confluence, and an atypical phenotype. The choice of detergents used for tissue decellularization can have a marked effect upon the integrity of the BMC of the resultant bioscaffold.
doi:10.1016/j.actbio.2013.09.006
PMCID: PMC3857635  PMID: 24055455
Re-endothelization; Organ engineering; Extracellular matrix; Biologic scaffold; Regenerative medicine; Decellularization
21.  Multifunctional role of osteopontin in directing intrafibrillar mineralization of collagen and activation of osteoclasts 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.10.010.
Mineralized collagen composites are of interest because they have the potential to provide a bone-like scaffold that stimulates the natural processes of resorption and remodeling. Working toward this goal, our group has previously shown that the nanostructure of bone can be reproduced using a polymer-induced liquid-precursor (PILP) process, which enables intrafibrillar mineralization of collagen with hydroxyapatite (HA) to be achieved. This prior work used polyaspartic acid (pASP), a simple mimic for acidic non-collagenous proteins (NCPs), to generate nanodroplets/nanoparticles of an amorphous mineral precursor which can infiltrate the interstices of type-I collagen fibrils. In this study we show that osteopontin (OPN) can similarly serve as a process-directing agent for the intrafibrillar mineralization of collagen, even though OPN is generally considered a mineralization inhibitor. We also found that inclusion of OPN in the mineralization process promotes the interaction of mouse marrow-derived osteoclasts with PILP-remineralized bone that was previously demineralized, as measured by actin ring formation. While osteoclast activation occurred when pASP was used as the process-directing agent, using OPN resulted in a dramatic effect on osteoclast activation, presumably because of the inherent arginine-glycine-aspartate acid (RGD) ligands of OPN. By capitalizing on the multifunctionality of OPN, these studies may lead the way to producing biomimetic bone substitutes with the capability of tailorable bioresorption rates.
doi:10.1016/j.actbio.2013.10.010
PMCID: PMC3864794  PMID: 24140612
Biomimetic material; biomineralization; bioresorption; bone graft; osteopontin; osteoclast
22.  Electrospun Scaffolds for Tissue Engineering of Vascular Grafts 
Acta biomaterialia  2013;10(1):10.1016/j.actbio.2013.08.022.
There is a growing demand for off-the-shelf tissue engineered vascular grafts (TEVGs) for replacement or bypass of damaged arteries in various cardiovascular diseases. Scaffolds from the decellularized tissue skeletons to biopolymers and biodegradable synthetic polymers have been used for fabricating TEVGs. However, several issues have not yet been resolved, which include the inability to mimic the mechanical properties of native tissues, and the ability for long term patency and growth required for in vivo function. Electrospinning is a popular technique for the production of scaffolds that has the potential to address these issues. However, its application to human TEVGs has not yet been achieved. This review provides an overview of tubular scaffolds that have been prepared by electrospinning with potential for TEVG applications.
doi:10.1016/j.actbio.2013.08.022
PMCID: PMC3867370  PMID: 23973391
electrospinning; tubular scaffolds; vascular grafts; tissue engineering; burst strength; compliance; mechanical properties
23.  Chemical Sintering Generates Uniform Porous Hyaluronic Acid Hydrogels 
Acta biomaterialia  2013;10(1):205-213.
Implantation of scaffolds for tissue repair has been met with limited success primarily due to the inability to achieve vascularization within the construct. Many strategies have shifted to incorporate pores into these scaffolds to encourage rapid cellular infiltration and subsequent vascular ingrowth. We utilized an efficient chemical sintering technique to create a uniform network of polymethyl methacrylate (PMMA) microspheres for porous hyaluronic acid hydrogel formation. The porous hydrogels generated from chemical sintering possessed comparable pore uniformity and interconnectivity as the commonly used non- and heat sintering techniques. Moreover, similar cell response to the porous hydrogels generated from each sintering approach was observed in cell viability, spreading, proliferation in vitro, as well as, cellular invasion in vivo. We propose chemical sintering of PMMA microspheres using a dilute acetone solution as an alternative method to generating porous hyaluronic acid hydrogels since it requires equal or ten-fold less processing time as the currently used non-sintering or heat sintering technique, respectively.
doi:10.1016/j.actbio.2013.10.002
PMCID: PMC3941472  PMID: 24120847
Hydrogel; Hyaluronic acid / hyaluronan; Porosity; Angiogenesis
24.  Composition of Intraperitoneally-Implanted Electrospun Conduits Modulates Cellular Elastic Matrix Generation 
Acta biomaterialia  2013;10(1):163-172.
Improving elastic matrix generation is critical to developing functional tissue engineered vascular grafts. Therefore, this study pursued a strategy to grow autologous tissue in vivo by recruiting potentially more elastogenic cells to conduits implanted within the peritoneal cavity. The goal was to determine the impacts of electrospun conduit composition and hyaluronan oligomer (HA-o) modification on the recruitment of peritoneal cells, and their phenotype and ability to synthesize elastic matrix. These responses were assessed as a function of conduit intraperitoneal implantation time. This study showed that the blending of collagen with poly(ε- caprolactone)(PCL) promotes a faster wound healing response, as assessed by trends in expression of macrophage and smooth muscle cell (SMC) contractile markers and in matrix deposition, compared to the more chronic response for PCL alone. This result, along with the increase in elastic matrix production, demonstrates the benefits of incorporating a little as 25% w/w collagen into the conduit. In addition, PCR analysis demonstrated the challenges in differentiating between a myofibroblast and a SMC using traditional phenotypic markers. Finally, the impact of the tethered HA-o is limited within the inflammatory environment, unlike the significant response found previously in vitro. In conclusion, these results demonstrate the importance of both careful control of implanted scaffold composition and the development of appropriate delivery methods for HA-o.
doi:10.1016/j.actbio.2013.08.042
PMCID: PMC4024661  PMID: 24016842
Elastin; Peritoneal Cavity; Electrospinning; Collagen; Hyaluronan; Vascular Grafts
25.  Low density biodegradable shape memory polyurethane foams for embolic biomedical applications 
Acta biomaterialia  2013;10(1):67-76.
Low density shape memory polymer foams hold significant interest in the biomaterials community for their potential use in minimally invasive embolic biomedical applications. The unique shape memory behavior of these foams allows them to be compressed to a miniaturized form, which can be delivered to an anatomical site via a transcatheter process, and thereafter actuated to embolize the desired area. Previous work in this field has described the use of a highly covalently crosslinked polymer structure for maintaining excellent mechanical and shape memory properties at the application-specific ultra low densities. This work is aimed at further expanding the utility of these biomaterials, as implantable low density shape memory polymer foams, by introducing controlled biodegradability. A highly covalently crosslinked network structure was maintained by use of low molecular weight, symmetrical and polyfunctional hydroxyl monomers such as Polycaprolactone triol (PCL-t, Mn 900 g), N,N,N0,N0-Tetrakis (hydroxypropyl) ethylenediamine (HPED), and Tris (2-hydroxyethyl) amine (TEA). Control over the degradation rate of the materials was achieved by changing the concentration of the degradable PCL-t monomer, and by varying the material hydrophobicity. These porous SMP materials exhibit a uniform cell morphology and excellent shape recovery, along with controllable actuation temperature and degradation rate. We believe that they form a new class of low density biodegradable SMP scaffolds that can potentially be used as “smart” non-permanent implants in multiple minimally invasive biomedical applications.
doi:10.1016/j.actbio.2013.09.027
PMCID: PMC4075478  PMID: 24090987
Shape Memory Polyurethane; Polycaprolactone triol; low density foams; degradation rate; FTIR

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