R-3 Repository :: Browsing by Author "Mikos, Antonios G."

Browsing by Author "Mikos, Antonios G."

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3D tissue-engineered model of Ewing's sarcoma
(Elsevier, 2014) Lamhamedi-Cherradi, Salah-Eddine; Santoro, Marco; Ramammoorthy, Vandhana; Menegaz, Brian A.; Bartholomeusz, Geoffrey; Iles, Lakesla R.; Amin, Hesham M.; Livingston, J. Andrew; Mikos, Antonios G.; Ludwig, Joseph A.
Despite longstanding reliance upon monolayer culture for studying cancer cells, and numerous advantages from both a practical and experimental standpoint, a growing body of evidence suggests that more complex three-dimensional (3D) models are necessary to properly mimic many of the critical hallmarks associated with the oncogenesis, maintenance and spread of Ewing's sarcoma (ES), the second most common pediatric bone tumor. And as clinicians increasingly turn to biologically-targeted therapies that exert their effects not only on the tumor cells themselves, but also on the surrounding extracellular matrix, it is especially important that preclinical models evolve in parallel to reliably measure antineoplastic effects and possible mechanisms of de novo and acquired drug resistance. Herein, we highlight a number of innovative methods used to fabricate biomimetic ES tumors, encompassing both the surrounding cellular milieu and the extracellular matrix (ECM), and suggest potential applications to advance our understanding of ES biology, preclinical drug testing, and personalized medicine.
A 3D inﾠvitro model of patient-derived prostate cancer xenograft for controlled interrogation of inﾠvivo tumor-stromal interactions
(Elsevier, 2016) Fong, Eliza L.S.; Wan, Xinhai; Yang, Jun; Morgado, Micaela; Mikos, Antonios G.; Harrington, Daniel Anton; Navone, Nora M.; Farach-Carson, Mary C.
Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co-culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa-osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa-osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions.
A factorial analysis of the combined effects of hydrogel fabrication parameters on the in vitro swelling and degradation of oligo(poly(ethylene glycol) fumarate) hydrogels
(Wiley, 2014) Lam, Johnny; Kim, Kyobum; Lu, Steven; Tabata, Yasuhiko; Scott, David W.; Mikos, Antonios G.; Kasper, F. Kurtis
In this study, a full factorial approach was used to investigate the effects of poly(ethylene glycol) (PEG) molecular weight (MW; 10,000 vs. 35,000 nominal MW), crosslinker-to-macromer carbon–carbon double bond ratio (DBR; 40 vs. 60), crosslinker type (PEG-diacrylate (PEGDA) vs. N,N′-methylene bisacrylamide (MB)), crosslinking extent of incorporated gelatin microparticles (low vs. high), and incubation medium composition (with or without collagenase) on the swelling and degradation characteristics of oligo[(poly(ethylene glycol) fumarate)] (OPF) hydrogel composites as indicated by the swelling ratio and the percentage of mass remaining, respectively. Each factor consisted of two levels, which were selected based on previous in vitro and in vivo studies utilizing these hydrogels for various tissue engineering applications. Fractional factorial analyses of the main effects indicated that the mean swelling ratio and the mean percentage of mass remaining of OPF composite hydrogels were significantly affected by every factor. In particular, increasing the PEG chain MW of OPF macromers significantly increased the mean swelling ratio and decreased the mean percentage of mass remaining by 5.7 ± 0.3 and 17.2 ± 0.6%, respectively. However, changing the crosslinker from MB to PEGDA reduced the mean swelling ratio and increased the mean percentage of mass remaining of OPF composite hydrogels by 4.9 ± 0.2 and 9.4 ± 0.9%, respectively. Additionally, it was found that the swelling characteristics of hydrogels fabricated with higher PEG chain MW or with MB were more sensitive to increases in DBR. Collectively, the main and cross effects observed between factors enables informed tuning of the swelling and degradation properties of OPF-based hydrogels for various tissue engineering applications.
A high-strength mineralized collagen bone scaffold for large-sized cranial bone defect repair in sheep
(Oxford University Press, 2018) Wang, Shuo; Zhao, Zhijun; Yang, Yongdong; Mikos, Antonios G.; Qiu, Zhiye; Song, Tianxi; Cui, Fuzhai; Wang, Xiumei; Zhang, Chunyang
Large-sized cranial bone defect repair presents a great challenge in the clinic. The ideal cranioplasty materials to realize the functional and cosmetic recovery of the defect must have sufficient mechanical support, excellent biocompatibility, good osseointegration and biodegradability as well. In this study, a high-strength mineralized collagen (MC) bone scaffold was developed with biomimetic composition, microstructure and mechanical properties for the repair of sheep large-sized cranial bone defects in comparison with two traditional cranioplasty materials, polymethyl methacrylate and titanium mesh. The compact MC scaffold showed no distinct pore structure and therefore possessed good mechanical properties. The strength and elastic modulus of the scaffold were much higher than those of natural cancellous bone and slightly lower than those of natural compact bone. In vitro cytocompatibility evaluation revealed that the human bone marrow mesenchymal stem cells (hBMSC) had good viability, attachment and proliferation on the compact MC scaffold indicating its excellent biocompatibility. An adult sheep cranial bone defect model was constructed to evaluate the performances of these cranioplasty materials in repairing the cranial bone defects. The results were investigated by gross observation, computed tomography scanning as well as histological assessments. The in vivo evaluations indicated that compact MC scaffold showed notable osteoconductivity and osseointegration with surrounding cranial bone tissues by promoting bone regeneration. Our results suggested that the compact MC scaffold has a promising potential for large-sized cranial bone defect repair.
A Multifaceted Approach to Enhance the Current Understanding and Treatment of Calcific Aortic Valve Disease
(2013-11-27) Wiltz, Dena; Grande-Allen, K. Jane; Gustin, Michael C.; Mikos, Antonios G.
Calcific aortic valve disease (CAVD) is a serious condition with unclear mechanisms driving this disease. This research focused on investigating the role of lysophosphatidylcholine (LPC) in CAVD and evaluating the efficacy of Raman spectroscopy (RS) to aid in current tissue engineering methods of heart valve replacements used to treat CAVD. Appropriate culture conditions for in vitro studies of CAVD were established. Specifically, the application of gentamicin in valvular interstitial cell (VIC) cultures was determined to significantly decrease mineralization of VICs in vitro in both normal and pre-calcified VIC culture conditions. Next, in vitro studies were conducted examining the role of LPC in a comparison of aortic and mitral VIC mineralization. Results indicated a higher percentage of LPC in calcified regions of tissue compared to non-calcified regions. In addition, 10000 nM LPC led to an increase in VIC mineralization, and aortic VICs displayed greater mineralization compared to mitral VICs. The role of the ryanodine receptor (RyR) in LPC-induced mineralization was evaluated. The presence of RyR isoforms 2 and 3 were confirmed in VICs. Next, in the presence of 10 µM LPC, the RyR was blocked and mineralization in VIC cultures significantly decreased compared to LPC treated cultures in which the RyR was not blocked. Several strategies exist for utilizing mesenchymal stem cells (MSCs) for tissue engineering of heart valves (TEHV) for valve replacement therapies. In this research, RS was able to detect distinct molecular characteristics of MSCs from different sources. This research has a significant impact on the study and understanding of CAVD. It suggests that gentamicin be used cautiously with in vitro studies of calcification, and suggest that mechanisms by which gentamicin acts in VICs may reverse calcification. In addition, these results showed that LPC has the capacity to promote VIC calcification, by interacting with the RyR, and that aortic VICs have a greater propensity for mineralization compared to mitral VICs. Also, RS may be used in future research to characterize MSCs prior to their use in TEHV. This research has highlighted the need for future investigations of LPC and the use of RS in understanding and treating CAVD.
A rapid, flexible method for incorporating controlled antibiotic release into porous polymethylmethacrylate space maintainers for craniofacial reconstruction
(Royal Society of Chemistry, 2016) Mountziaris, Paschalia M.; Shah, Sarita R.; Lam, Johnny; Bennett, George N.; Mikos, Antonios G.
Severe injuries in the craniofacial complex, resulting from trauma or pathology, present several challenges to functional and aesthetic reconstruction. The anatomy and position of the craniofacial region make it vulnerable to injury and subsequent local infection due to external bacteria as well as those from neighbouring structures like the sinuses, nasal passages, and mouth. Porous polymethylmethacrylate (PMMA) “space maintainers” have proven useful in staged craniofacial reconstruction by promoting healing of overlying soft tissue prior to reconstruction of craniofacial bones. We describe herein a method by which the porosity of a prefabricated porous PMMA space maintainer, generated by porogen leaching, can be loaded with a thermogelling copolymer-based drug delivery system. Porogen leaching, space maintainer prewetting, and thermogel loading all significantly affected the loading of a model antibiotic, colistin. Weeks-long release of antibiotic at clinically relevant levels was achieved with several formulations. In vitro assays confirmed that the released colistin maintained its antibiotic activity against several bacterial targets. Our results suggest that this method is a valuable tool in the development of novel therapeutic approaches for the treatment of severe complex, infected craniofacial injuries.
A unique biomimetic modification endows polyetherketoneketone scaffold with osteoinductivity by activating cAMP/PKA signaling pathway
(AAAS, 2022) Yuan, Bo; Zhang, Yuxiang; Zhao, Rui; Lin, Hai; Yang, Xiao; Zhu, Xiangdong; Zhang, Kai; Mikos, Antonios G.; Zhang, Xingdong
Osteoinductivity of a biomaterial scaffold can notably enhance the bone healing performance. In this study, we developed a biomimetic and hierarchically porous polyetherketoneketone (PEKK) scaffold with unique osteoinductivity using a combined surface treatment strategy of a sulfonated process and a nano bone-like apatite deposition. In a beagle intramuscular model, the scaffold induced bone formation ectopically after 12-week implantation. The better bone healing ability of the scaffold than the original PEKK was also confirmed in orthotopic sites. After culturing with bone marrow–derived mesenchymal stem cells (BMSCs), the scaffold induced osteogenic differentiation of BMSCs, and the new bone formation could be mainly depending on cell signaling through adenylate cyclase 9, which activates the cyclic adenosine monophosphate/protein kinase A signaling cascade pathways. The current work reports a new osteoinductive synthetic polymeric scaffold with its detailed molecular mechanism of action for bone repair and regeneration.
Antibiotic-releasing Porous Poly(methyl methacrylate) for Space Maintenance and Infection Prevention in Large Bone Defects
(2016-07-29) Shah, Sarita R.; Mikos, Antonios G.
Large tissue defects in the mandible or long bones resulting from trauma or pathology present many challenges to tissue engineers attempting to regenerate lost tissue. These defects present anatomical challenges to regeneration as well as complicating factors, primarily infection. Because infection is a common and debilitating complication, we sought to develop an antibiotic-releasing porous space maintainer as part of a two-stage reconstructive approach that can support the preservation and optimization of large bone defects to facilitate later reconstruction. These porous space maintainers comprise a bulk phase of non-degradable poly(methyl methacrylate) (PMMA) made porous with an aqueous gel porogen. High local concentrations of antibiotic can be achieved by incorporation of drug into the space maintainer and release kinetics can be modified by utilizing different materials for release. In this thesis, we first present the development of poly(lactic-co-glycolic acid) (PLGA) microparticles as a platform for the controlled release of multiple types of antibiotic. We demonstrate in this specific aim that antibiotic physicochemical properties can be used to infer general loading efficiency and release kinetics, providing guidance for efficient decision-making regarding antibiotics suitable for delivery via PLGA microparticles. The second objective of this work was to evaluate antibiotic-loaded porous space maintainers in vivo with regards to the effect of antibiotic dose and release kinetics on bacterial clearance and tissue healing in the craniofacial region using an infected rabbit mandibular defect model. The results from in vitro evaluation demonstrate that the release of antibiotics from porous space maintainers can be controlled by incorporating PLGA microparticles. Furthermore, in vivo evaluation shows that antibiotic dose and release kinetics have significant effects on local tissues and and that these effects may be unique to each antibiotic type, highlighting the importance of evaluating tissue response to antibiotic-releasing constructs in addition to antimicrobial efficacy. In the third specific aim, we evaluated the effects of bacterial contamination and local clindamycin delivery on bacterial clearance and the regenerative potential of an induced in an infected rat femoral defect model. The results from this specific aim demonstrated that local antibiotic delivery influences the gene expression profile of local regenerating tissues and therefore can be leveraged for its effects on host tissues as well as its antimicrobial properties. Finally, we anticipated the future use of space maintainers for one-stage reconstruction. The degradable polymer poly(propylene fumarate) (PPF) was evaluated as a candidate for a degradable antibiotic-releasing porous space maintainer. The results from this study demonstrated that fabrication parameters such as polymer-to-crosslinker ratio and the percent incorporation of PLGA microparticles can be modified to tune the properties of antibiotic-releasing degradable space maintainers suitable for one-stage reconstruction. The overall goal of this work was to develop antibiotic-releasing porous space maintainers as a strategy to support the reconstruction of contaminated bone defects at risk of infection. Through this thesis, we have demonstrated that local antibiotic delivery is a promising strategy for preventing the progression of contamination to infection and that antibiotic dose and release kinetics can be further leveraged to alter local tissue response.
Articular chondrocytes and mesenchymal stem cells seeded on biodegradable scaffolds for the repair of cartilage in a rat osteochondral defect model
(Elsevier, 2014) Dahlin, Rebecca L.; Kinard, Lucas A.; Lam, Johnny; Needham, Clark J.; Lu, Steven; Kasper, F. Kurtis; Mikos, Antonios G.
This work investigated the ability of co-cultures of articular chondrocytes and mesenchymal stem cells (MSCs) to repair articular cartilage in osteochondral defects. Bovine articular chondrocytes and rat MSCs were seeded in isolation or in co-culture onto electrospun poly(ɛ-caprolactone) (PCL) scaffolds and implanted into an osteochondral defect in the trochlear groove of 12-week old Lewis rats. Additionally, a blank PCL scaffold and untreated defect were investigated. After 12 weeks, the extent of cartilage repair was analyzed through histological analysis, and the extent of bone healing was assessed by quantifying the total volume of mineralized bone in the defect through microcomputed tomography. Histological analysis revealed that the articular chondrocytes and co-cultures led to repair tissue that consisted of more hyaline-like cartilage tissue that was thicker and possessed more intense Safranin O staining. The MSC, blank PCL scaffold, and empty treatment groups generally led to the formation of fibrocartilage repair tissue. Microcomputed tomography revealed that while there was an equivalent amount of mineralized bone formation in the MSC, blank PCL, and empty treatment groups, the defects treated with chondrocytes or co-cultures had negligible mineralized bone formation. Overall, even with a reduced number of chondrocytes, co-cultures led to an equal level of cartilage repair compared to the chondrocyte samples, thus demonstrating the potential for the use of co-cultures of articular chondrocytes and MSCs for the in vivo repair of cartilage defects.
Autologously Generated Tissue-Engineered Bone Flaps for Reconstruction of Large Mandibular Defects in an Ovine Model
(Mary Ann Liebert, Inc., 2015) Tatara, Alexander M.; Kretlow, James D.; Spicer, Patrick P.; Lu, Steven; Lam, Johnny; Liu, Wei; Cao, Yilin; Liu, Guangpeng; Jackson, John D.; Yoo, James J.; Atala, Anthony; van den Beucken, Jeroen J.J.P.; Jansen, John A.; Kasper, F. Kurtis; Ho, Tang; Demian, Nagi; Miller, Michael John; Wong, Mark E.; Mikos, Antonios G.
The reconstruction of large craniofacial defects remains a significant clinical challenge. The complex geometry of facial bone and the lack of suitable donor tissue often hinders successful repair. One strategy to address both of these difficulties is the development of an in vivo bioreactor, where a tissue flap of suitable geometry can be orthotopically grown within the same patient requiring reconstruction. Our group has previously designed such an approach using tissue chambers filled with morcellized bone autograft as a scaffold to autologously generate tissue with a predefined geometry. However, this approach still required donor tissue for filling the tissue chamber. With the recent advances in biodegradable synthetic bone graft materials, it may be possible to minimize this donor tissue by replacing it with synthetic ceramic particles. In addition, these flaps have not previously been transferred to a mandibular defect. In this study, we demonstrate the feasibility of transferring an autologously generated tissue-engineered vascularized bone flap to a mandibular defect in an ovine model, using either morcellized autograft or synthetic bone graft as scaffold material.
Biocompatible macromers
(2005-04-26) Jo, Seongbong; Mikos, Antonios G.; Rice University; United States Patent and Trademark Office
A new oligomer based on alternating fumaric acid and poly(ethylene glycol) (PEG) units is provided. The oligo(PEG fumarate) (OPF) may be functionalized by modification with a biocompatible organic group. Further, the OPF may be cross-linked using radical polymerization in the presence of either a chemical or photo initiator. A cross-linked OPF gel has a swelling behavior that is tunable dependent on the molecular weight of PEG. A cross-linkable PEG macromer, as exemplified by oligo(PEG fumarate), has unsaturated double bonds, for example in the fumaryl groups, along its macromolecular chain that allows for the preparation of hydrogels with tailored structure and properties.
Biodegradable bone templates
(1996-06-04) Mikos, Antonios G.; Rice University; United States Patent and Trademark Office
A biodegradable, bioresorbable, three-dimensional template for repair and replacement of diseased or injured bone which provides mechanical strength to bone while also providing a guide for growth of bone tissue. Preferably, the template is formed of biodegradable materials, for example, poly(L-lactic acid), poly(D, L-lactic acid), poly (D, L-lactic-co-glycolic acid), poly (glycolic acid), poly (ε-caprolactone), polyortho esters, and polyanhydrides, and has the capacity of being rendered porous, either in vitro or in vivo. A pore-forming component, which may or may not be a polymeric material, is mixed within a continuous matrix formed of a biodegradable material, the pore-forming component having a rate of degradation which exceeds that of the matrix. Differential dissolution or biodegradation provides porosity to the template.
Biodegradable branched polycationic polymers as non-viral gene delivery vectors for bone tissue engineering
(2010) Chew, Sue Anne; Mikos, Antonios G.
In this work, biodegradable branched triacrylate/amine polycationic polymers (TAPPs) were synthesized from different amine and triacrylate monomers by Michael addition polymerization and incorporated into a composite scaffold to evaluate these polymers in a bone tissue engineering system. The effects of the hydrophilic spacer lengths in the polymer on characteristics which are important for gene delivery were evaluated by varying the triacrylate monomer used in the synthesis. The results demonstrated that hydrophilic spacers can be incorporated into polycationic polymers to reduce their cytotoxicity and enhance the degradability. The effects of amine basicities in the polymer on characteristics which are important for gene delivery were also evaluated by varying the amine monomers used in the synthesis. The results indicated that polycationic polymers with amines that dissociate above pH 7.4, which are available as positively charged groups for plasmid DNA (pDNA) complexation at pH 7.4, can be synthesized to produce stable polyplexes with increased zeta potential and decreased hydrodynamic size that efficiently transfect cells. TAPP/pDNA polyplexes were then incorporated into a composite containing gelatin microparticles (GMPs) and a porous poly(propylene fumarate) scaffold. The release of pDNA in vitro was not affected by the crosslinking density of the GMPs but depended, instead, on the degradation rates of the TAPPs. Besides the initial burst release of polyplexes not bounded to the GMPs and the minimal release of pDNA through diffusion and dissociation from the GMPs, the pDNA was likely released as naked pDNA or in an incomplete polyplex as fragments of the polymer had to degrade to release the pDNA. The results indicated that polymeric vectors with a lower degradation rate can prolong the release of pDNA from the composite scaffold. Composite scaffolds loaded with TAPP/pDNA polyplexes may not have delivered enough intact polyplexes, as enhanced bone formation was not observed in a critical-size rat cranial defect at 12 weeks postimplantation compared to those loaded with naked pDNA. A gene delivery system consisting of biodegradable polycationic polymers should be designed to release the pDNA in an intact polyplex form.
Biodegradable poly (propylene fumarate) networks cross linked with poly (propylene fumarate) -diacrylate macromers
(2004-07-06) He, Shulin; Yaszemski, Michael J.; Mikos, Antonios G.; Rice University; United States Patent and Trademark Office
A network consisting essentially of poly(propylene fumarate) cross linked with diacrylate and a method for making same.
Biodegradable poly(propylene fumarate) networks cross linked with poly(propylene fumarate)-diacrylate macromers
(2002-07-23) He, Shulin; Yaszemski, Michael J.; Mikos, Antonios G.; Rice University; United States Patent and Trademark Office
A network consisting essentially of poly(propylene fumarate) cross linked with diacrylate and a method for making same.
Biodegradable, phosphate-containing, dual-gelling macromers for cellular delivery in bone tissue engineering
(Elsevier, 2015) Watson, Brendan M.; Vo, Tiffany N.; Tatara, Alexander M.; Shah, Sarita R.; Scott, David W.; Engel, Paul S.; Mikos, Antonios G.
Injectable, biodegradable, dual-gelling macromer solutions were used to encapsulate mesenchymal stem cells (MSCs) within stable hydrogels when elevated to physiologic temperature. Pendant phosphate groups were incorporated in the N-isopropyl acrylamide-based macromers to improve biointegration and facilitate hydrogel degradation. The MSCs were shown to survive the encapsulation process, and live cells were detected within the hydrogels for up to 28 days inﾠvitro. Cell-laden hydrogels were shown to undergo significant mineralization in osteogenic medium. Cell-laden and acellular hydrogels were implanted into a critical-size rat cranial defect for 4 and 12 weeks. Both cell-laden and acellular hydrogels were shown to degrade inﾠvivo and help to facilitate bone growth into the defect. Improved bone bridging of the defect was seen with the incorporation of cells, as well as with higher phosphate content of the macromer. Furthermore, direct bone-to-hydrogel contact was observed in the majority of implants, which is not commonly seen in this model. The ability of these macromers to deliver stem cells while forming in situ and subsequently degrade while facilitating bone ingrowth into the defect makes this class of macromers a promising material for craniofacial bone tissue engineering.
Bioinspired electrospun dECM scaffolds guide cell growth and control the formation of myotubes
(AAAS, 2021) Smoak, Mollie M.; Hogan, Katie J.; Grande-Allen, K. Jane; Mikos, Antonios G.
While skeletal muscle has a high capacity for endogenous repair in acute injuries, volumetric muscle loss can leave long-lasting or permanent structural and functional deficits to the injured muscle and surrounding tissues. With clinical treatments failing to repair lost tissue, there is a great need for a tissue-engineered therapy to promote skeletal muscle regeneration. In this study, we aim to assess the potential for electrospun decellularized skeletal muscle extracellular matrix (dECM) with tunable physicochemical properties to control mouse myoblast growth and myotube formation. The material properties as well as cell behavior – growth and differentiation – were assessed in response to modulation of crosslinking and scaffold architecture. The fabrication of a bioactive dECM-based system with tunable physicochemical properties that can control myotube formation has several applications in skeletal muscle engineering and may bring the field one step closer to developing a therapy to address these unmet clinical needs. Electrospun decellularized skeletal muscle with tunable physicochemical properties controls myoblast growth and myotube formation. Electrospun decellularized skeletal muscle with tunable physicochemical properties controls myoblast growth and myotube formation.
Biomaterial-based strategies for craniofacial tissue engineering
(2010) Kretlow, James D.; Mikos, Antonios G.
Damage to or loss of craniofacial tissues, often resulting from neoplasm, trauma, or congenital defects, can have devastating physical and psychosocial effects. The presence of many specialized tissue types integrated within a relatively small volume leads to difficulty in achieving complete functional and aesthetic repair. Tissue engineering offers a promising alternative to conventional therapies by potentially enabling the regeneration of normal native tissues. Initially, a stimulus responsive biomaterial designed for injectable cell delivery applications was investigated with the goal of providing a substrate for osteogenic differentiation of delivered cells. In order to enable faster clinical translation, later efforts focused on novel combinations of regulated materials. Most common approaches using cell delivery for bone tissue engineering involve the harvest and ex vivo expansion of progenitor cell populations over multiple weeks and cell passages. The effect of aging and passage on proliferation and differentiation were analyzed using murine mesenchymal stem cells as a model. These cells lose their ability to proliferate and differentiate with increases in donor age and passages during cell culture. Delivery of uncultured bone marrow mononuclear cells was then investigated, and it was determined that when delivered to porous scaffolds these cells, which can be harvested, isolated, and returned to the body within the setting of a single operation, significantly increased bone regeneration in vivo. Finally, because these techniques of scaffold implantation and cell delivery would likely fail if delivered to an exposed or infected wound, a method of space maintenance was investigated. Space maintainers made of poly(methyl methacrylate) and having tunable porosity and pore interconnectivity were evaluated within a clean/contaminated mandibular defect. Low porosity space maintainers were found to prevent soft tissue collapse or contracture into the bony defect and allowed surrounding soft tissues to penetrate the pores of the implant, enabling healing over 12 weeks. The tissue response and wound healing characteristics of these implant was favorable when compared to solid or high porosity implants. Although optimization and further investigation of these techniques is necessary, in combination these approaches demonstrate one possible and translatable approach towards craniofacial tissue regeneration.
Biomechanical forces in tissue engineered tumor models
(Elsevier, 2018) Chim, Letitia K.; Mikos, Antonios G.
Solid tumors are complex three-dimensional (3D) networks of cancer and stromal cells within a dynamic extracellular matrix. Monolayer cultures fail to recapitulate the native microenvironment and therefore are poor candidates for pre-clinical drug studies and studying pathways in cancer. The tissue engineering toolkit allows us to make models that better recapitulate the 3D architecture present in tumors. Moreover, the role of the mechanical microenvironment, including matrix stiffness and shear stress from fluid flow, is known to contribute to cancer progression and drug resistance. We review recent developments in tissue engineered tumor models with a focus on the role of the biomechanical forces and propose future considerations to implement to improve physiological relevance of such models.
Bismuth@US-tubes as a potential contrast agent for X-ray imaging applications
(Royal Society of Chemistry, 2013) Rivera, Eladio J.; Tran, Lesa A.; Hernández-Rivera, Mayra; Yoon, Diana; Mikos, Antonios G.; Rusakova, Irene A.; Cheong, Benjamin Y.; Cabreira-Hansen, Maria da Graça; Willerson, James T.; Perin, Emerson C.; Wilson, Lon J.; Richard E. Smalley Institute for Nanoscale Science & Technology
The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking.

Browsing by Author "Mikos, Antonios G."

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