Isha Mutreja | University of Minnesota - Twin Cities (original) (raw)

Papers by Isha Mutreja

Research paper thumbnail of Lipid nanoparticle-based formulations for high-performance dentistry applications

Journal of Materials Chemistry B

This review provides a comprehensive discussion on the synthesis and application of different lip... more This review provides a comprehensive discussion on the synthesis and application of different lipid nanoformulations in dentistry while highlighting the challenges and alternative approaches for improved functional efficacy.

Research paper thumbnail of LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research

Journal of Materials Chemistry B

Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and... more Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and surface chemistry to work as a therapeutic delivery agent and a diagnostic tool for non-invasive real-time monitoring using SPCCT imaging technology.

Research paper thumbnail of Biofabrication of Modular Spheroids as Tumor‐Scale Microenvironments for Drug Screening

Advanced Healthcare Materials

Research paper thumbnail of Correction: Lipid nanoparticle-based formulations for high-performance dentistry applications

Journal of Materials Chemistry B

Correction for ‘Lipid nanoparticle-based formulations for high-performance dentistry applications... more Correction for ‘Lipid nanoparticle-based formulations for high-performance dentistry applications’ by Isha Mutreja et al., J. Mater. Chem. B, 2023, https://doi.org/10.1039/D3TB00431G.

Research paper thumbnail of A Novel Dental Polymer with a Flipped External Ester Group Design that Resists Degradation via Polymer Backbone Preservation

Current dental sealants with methacrylate based chemistry are prone to hydrolytic degradation. A ... more Current dental sealants with methacrylate based chemistry are prone to hydrolytic degradation. A conventional ethylene glycol dimethacrylate (EGDMA) was compared to a novel methacrylate monomer with a flipped external ester group (ethylene glycol ethyl methacrylate-EGEMA) that was designed to resist polymer degradation effects. Fourier transform infrared spectroscopy and water contact angle confirmed a comparable degree of initial conversion and surface wettability for EGDMA and EGEMA. EGDMA disks initially performed better compared to EGEMA as suggested by higher surface hardness and 1.5 times higher diametral tensile strength (DTS). After 15 weeks of hydrolytic and accelerated aging, EGDMA and EGEMA DTS was reduced by 88% and 44% respectively. This accelerated aging model resulted in 3.3 times higher water sorption for EDGMA than EGEMA disks. EGDMA had an increase in grain boundary defects and visible erosion sites with accelerated aging, while for EGEMA the changes were not significant.

Research paper thumbnail of Gelatin Methacryloyl Hydrogels for Musculoskeletal Tissue Regeneration

Bioengineering

Musculoskeletal disorders are a significant burden on the global economy and public health. Hydro... more Musculoskeletal disorders are a significant burden on the global economy and public health. Hydrogels have significant potential for enhancing the repair of damaged and injured musculoskeletal tissues as cell or drug delivery systems. Hydrogels have unique physicochemical properties which make them promising platforms for controlling cell functions. Gelatin methacryloyl (GelMA) hydrogel in particular has been extensively investigated as a promising biomaterial due to its tuneable and beneficial properties and has been widely used in different biomedical applications. In this review, a detailed overview of GelMA synthesis, hydrogel design and applications in regenerative medicine is provided. After summarising recent progress in hydrogels more broadly, we highlight recent advances of GelMA hydrogels in the emerging fields of musculoskeletal drug delivery, involving therapeutic drugs (e.g., growth factors, antimicrobial molecules, immunomodulatory drugs and cells), delivery approaches...

Research paper thumbnail of Methacrylate Polymers With “Flipped External” Ester Groups: A Review

Frontiers in Dental Medicine

Current resin composites have favorable handling and upon polymerization initial physical propert... more Current resin composites have favorable handling and upon polymerization initial physical properties that allow for efficient material replacement of removed carious tooth structure. Dental resin composites have long term durability limitations due to the hydrolysis of ester bonds within the methacrylate based polymer matrix. This article outlines the importance of ester bonds positioned internal to the carbon-carbon double bond in current methacrylate monomers. Water and promiscuous salivary/bacterial esterase activity can initiate ester bond hydrolysis that can sever the polymer backbone throughout the material. Recent studies have custom synthesized, with the latest advances in modern organic chemical synthesis, a novel molecule named ethylene glycol bis (ethyl methacrylate) (EGEMA). EGEMA was designed to retain the reactive acrylate units. Upon intermolecular polymerization of vinyl groups, EGEMA ester groups are positioned outside the backbone of the polymer chain. This review ...

Research paper thumbnail of Hybrid nanocoatings of self-assembled organic-inorganic amphiphiles for prevention of implant infections

Acta Biomaterialia, 2022

Antimicrobial coatings are one of the most promising strategies to prevent bacterial infections i... more Antimicrobial coatings are one of the most promising strategies to prevent bacterial infections in orthopedic and dental implants. Combining antimicrobial agents with different antimicrobial mechanisms might have synergistic effects and be more potent. Others have shown that nanocomposites of silver nanoparticles (AgNPs) decorated with antimicrobial peptides (AMPs) show increased potency as free agents in solution. However, similar nanocomposites have not been explored to coat biomaterials through cooperative weak electrostatic attraction forces between AMP, AgNPs and substrates in need of protection against infection. In this work, we synthesized self-assembled antimicrobial amphiphiles of an AMP, GL13K. Then, we decorated the AMP nanostructures with AgNPs, which were finally used to coat etched Ti (eTi) surfaces. The strong hydrogen bonding between the AMP amphiphiles and the polar eTi yielded a robust and stable coating. When compared to single AgNP or single AMP coatings, our hybrid nanocoatings had notably higher in vitro antimicrobial potency against multiple bacteria strains related to implant infection. The hybrid coating also showed relevant antimicrobial activity in an in vivo subcutaneous infection model in rats. This work advances the application of AgNP/AMP nanocomposites as effective coatings for prevention of implant infections. STATEMENT OF SIGNIFICANCE: : High morbidity, mortality and elevated costs are associated with orthopedic and dental implant infections. Conventional antibiotic treatment is ineffective due to barrier-like extracellular polysaccharide substances in biofilms and the increasing threat from antibiotic resistance. Antimicrobial coatings are one of the most promising strategies, but the performance is usually unsatisfactory, especially when tested in vivo. Here, we present a hybrid nanocoating with different modes of action to prevent implant infections using self-assembled antimicrobial peptide (AMP) amphiphiles decorated with silver nanoparticles (AgNPs). When compared to single AgNP or AMP coatings, our hybrid nanocoatings showed significant increases in antimicrobial potency against multiple implant infection-related bacterial strains in vitro and in an in vivo rat subcutaneous infection model.

Research paper thumbnail of Culture and characterization of various porcine integumentary-connective tissue-derived mesenchymal stromal cells to facilitate tissue adhesion to percutaneous metal implants

Stem Cell Research & Therapy, 2021

Background Transdermal osseointegrated prosthesis have relatively high infection rates leading to... more Background Transdermal osseointegrated prosthesis have relatively high infection rates leading to implant revision or failure. A principle cause for this complication is the absence of a durable impervious biomechanical seal at the interface of the hard structure (implant) and adjacent soft tissues. This study explores the possibility of recapitulating an analogous cellular musculoskeletal-connective tissue interface, which is present at naturally occurring integumentary tissues where a hard structure exits the skin, such as the nail bed, hoof, and tooth. Methods Porcine mesenchymal stromal cells (pMSCs) were derived from nine different porcine integumentary and connective tissues: hoof-associated superficial flexor tendon, molar-associated periodontal ligament, Achilles tendon, adipose tissue and skin dermis from the hind limb and abdominal regions, bone marrow and muscle. For all nine pMSCs, the phenotype, multi-lineage differentiation potential and their adhesiveness to clinical ...

Research paper thumbnail of Utilizing a degradation prediction pathway system to understand how a novel methacrylate derivative polymer with flipped external ester groups retains physico-mechanical properties following esterase exposure

Dental Materials, 2021

The region of failure for current methacrylates (i.e. derivatives of acrylates) are ester bond li... more The region of failure for current methacrylates (i.e. derivatives of acrylates) are ester bond linkages that hydrolyze in the presence of salivary and bacterial esterases that break the polymer network backbone. This effect decreases the mechanical properties of methacrylate-based materials. The ethylene glycol dimethacrylate (EGDMA) or novel ethylene glycol ethyl methacrylate (EGEMA) discs were prepared using 40 µL of the curing mixture containing photo/co-initiators for 40 s in a PTFE mold at 1000 mW/cm2. The degree of conversion was used as a quality control measure for the prepared discs, followed by physical, mechanical, and chemical characterization of discs properties before and after cholesterol esterase treatment. After 9 weeks of standardized cholesterol esterase (CEase) exposure, EGDMA discs showed exponential loss of material (p = 0.0296), strength (p = 0.0014) and increased water sorption (p = 0.0002) compared to EGEMA discs. We integrated a degradation prediction pathway system to LC/MS and GC/MS analyses to elucidate the degradation by-products of both EGEMA and EGDMA polymers. GC/MS analysis demonstrated that the esterase catalysis was directed to central polymer backbone breakage, producing ethylene glycol, for EGDMA, and to side chain breakage, producing ethanol, for EGEMA. The flipped external ester group linkage design is attributed to EGEMA showing higher resistance to esterase biodegradation and changes in mechanical and physical properties than EGDMA. EGEMA is a potential substitute for common macromer diluents, such as EGDMA, based on its resistance to biodegradation effects. This work inspires the flipped external group design to be applied to analogs of current larger, hydrophobic strength bearing macromers used in future dental material formulations.

Research paper thumbnail of Response of osteoblast cells to titanium and hydroxyapatite sputter deposited polystyrene

Research paper thumbnail of A novel methacrylate derivative polymer that resists bacterial cell‐mediated biodegradation

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2021

This study tests biodegradation resistance of a custom synthesized novel ethylene glycol ethyl me... more This study tests biodegradation resistance of a custom synthesized novel ethylene glycol ethyl methacrylate (EGEMA) with ester bond linkages that are external to the central polymer backbone when polymerized. Ethylene glycol dimethacrylate (EGDMA) with internal ester bond linkages and EGEMA discs were prepared in a polytetrafluoroethylene (PTFE) mold using 40 μl macromer and photo/co-initiator mixture cured for 40 s at 1000 mW/cm2 . The discs were stored in the constant presence of Streptococcus mutans (S. mutans) in Todd Hewitt Yeast + Glucose (THYE+G) media up to 9 weeks (n = 8 for each macromer type) and physical/mechanical properties were assessed. Initial measurements EGEMA versus EGDMA polymer discs showed equivalent degree of conversion (45.69% ± 2.38 vs. 46.79% ± 4.64), diametral tensile stress (DTS; 8.12± 2.92 MPa vs. 6.02 ± 1.48 MPa), and low subsurface optical defects (0.41% ± 0.254% vs. 0.11% ± 0.074%). The initial surface wettability (contact angle) was slightly higher (p ≤ .012) for EGEMA (62.02° ± 3.56) than EGDMA (53.86° ± 5.61°). EGDMA showed higher initial Vicker's hardness than EGEMA (8.03 ± 0.88 HV vs. 5.93 ± 0.69 HV; p ≤ .001). After 9 weeks of S. mutans exposure, EGEMA (ΔDTS-1.30 MPa) showed higher resistance to biodegradation effects with a superior DTS than EGDMA (ΔDTS-6.39 MPa) (p = .0039). Visible and scanning electron microscopy images of EGEMA show less surface cracking and defects than EGDMA. EGDMA had higher loss of material (18.9% vs. 8.5%, p = .0009), relative changes to fracture toughness (92.5% vs. 49.2%, p = .0022) and increased water sorption (6.1% vs. 1.9%, p = .0022) compared to EGEMA discs. The flipped external ester group linkage design is attributed to EGEMA showing higher resistance to bacterial degradation effects than an internal ester group linkage design methacrylate.

Research paper thumbnail of Micro- and Nanopatterning of Freestanding Protein Films

Biodegradable casein films have significant potential for use as non-supported stand-alone sheeti... more Biodegradable casein films have significant potential for use as non-supported stand-alone sheeting in orthopaedic implants and tissue engineering substrates. Multi-scale surface patterns can be used to modulate and guide cell interaction by means of an engineered construct. The majority of work on cell-pattern interaction has so far focused on non-degradable materials. In this paper we demonstrate for the first time the fabrication of microand nano-scale geometric patterns on the surface of a crosslinked biodegradable casein film. To achieve this we introduce a two-step fabrication procedure based on polydimethylsiloxane (PDMS) softlithography. We will show the reproduction of microand nanoscale patterns in liquid-cast casein films. We also demonstrate film formation and cross-linking using glutaraldehyde and discuss the use of these films as cell-culture substrates.

Research paper thumbnail of Cell responses to titanium and titanium alloys

Commercially pure titanium and titanium alloys have been extensively used for designing musculosk... more Commercially pure titanium and titanium alloys have been extensively used for designing musculoskeletal implants due to their biocompatibility and mechanical properties. The clinical success of these implants relies on supporting favorable osteoimmune environment, which then regulates bone regeneration and evades bacterial infection. Several surface engineering strategies have been employed to impart multifunctional properties to the otherwise bioinert titanium and titanium alloys. This chapter outlines these strategies, which encompass physical and chemical modification and their downstream effects on cell responses. In particular, we introduce the effect of these modifications on cells from hard and soft tissue along with their antibacterial properties and immune-modulatory effects. This chapter provides an up-to-date summary of where we are and how the understanding of the cellular response in vitro can help up drive the implant design for effective tissue repair and regeneration...

Research paper thumbnail of Hybrid biofabrication of 3D osteoconductive constructs comprising Mg-based nanocomposites and cell-laden bioinks for bone repair

Bone, 2021

Tissue engineering approaches for bone repair have rapidly evolved due to the development of nove... more Tissue engineering approaches for bone repair have rapidly evolved due to the development of novel biofabrication technologies, providing an opportunity to fabricate anatomically-accurate living implants with precise placement of specific cell types. However, limited availability of biomaterial inks, that can be 3D-printed with high resolution, while providing high structural support and the potential to direct cell differentiation and maturation towards the osteogenic phenotype, remains an ongoing challenge. Aiming towards a multifunctional biomaterial ink with high physical stability and biological functionality, this work describes the development of a nanocomposite biomaterial ink (Mg-PCL) comprising of magnesium hydroxide nanoparticles (Mg) and polycaprolactone (PCL) thermoplastic for 3D printing of strong and bioactive bone regenerative scaffolds. We characterised the Mg nanoparticle system and systematically investigated the cytotoxic and osteogenic effects of Mg supplementation to human mesenchymal stromal cells (hMSCs) 2D-cultures. Next, we prepared Mg-PCL biomaterial ink using a solvent casting method, and studied the effect of Mg over mechanical properties, printability and scaffold degradation. Furthermore, we delivered MSCs within Mg-PCL scaffolds using a gelatin-methacryloyl (GelMA) matrix, and evaluated the effect of Mg over cell viability and osteogenic differentiation. Nanocomposite Mg-PCL could be printed with high fidelity at 20 wt% of Mg content, and generated a mechanical reinforcement between 30%-400% depending on the construct internal geometry. We show that Mg-PCL degrades faster than standard PCL in an accelerated-degradation assay, which has positive implications towards in vivo implant degradation and bone regeneration. Mg-PCL did not affect MSCs viability, but enhanced osteogenic differentiation and bone-specific matrix deposition, as demonstrated by higher ALP/DNA levels and Alizarin Red calcium staining. Finally, we present proof of concept of Mg-PCL being utilised in combination with a bone-specific bioink (Sr-GelMA) in a coordinated-extrusion bioprinting strategy for fabrication of hybrid constructs with high stability and synergistic biological functionality. Mg-PCL further enhanced the osteogenic differentiation of encapsulated MSCs and supported bone ECM deposition within the bioink component of the hybrid construct, evidenced by mineralised nodule formation, osteocalcin (OCN) and collagen type-I (Col I) expression within the bioink filaments. This study demonstrated that magnesium-based nanocomposite bioink material optimised for extrusion-based 3D printing of bone regenerative scaffolds provide enhanced mechanical stability and bone-related bioactivity with promising potential for skeletal tissue regeneration.

Research paper thumbnail of Biomimetic mineralized hybrid scaffolds with antimicrobial peptides

Bioactive Materials, 2021

Infection in hard tissue regeneration is a clinically-relevant challenge. Development of scaffold... more Infection in hard tissue regeneration is a clinically-relevant challenge. Development of scaffolds with dual function for promoting bone/dental tissue growth and preventing bacterial infections is a critical need in the field. Here we fabricated hybrid scaffolds by intrafibrillar-mineralization of collagen using a biomimetic process and subsequently coating the scaffold with an antimicrobial designer peptide with cationic and amphipathic properties. The highly hydrophilic mineralized collagen scaffolds provided an ideal substrate to form a dense and stable coating of the antimicrobial peptides. The amount of hydroxyapatite in the mineralized fibers modulated the rheological behavior of the scaffolds with no influence on the amount of recruited peptides and the resulting increase in hydrophobicity. The developed scaffolds were potent by contact killing of Gram-negative Escherichia coli and Gram-positive Streptococcus gordonii as well as cytocompatible to human bone marrow-derived mesenchymal stromal cells. The process of scaffold fabrication is versatile and can be used to control mineral load and/ or intrafibrillar-mineralized scaffolds made of other biopolymers. Peer review under responsibility of KeAi Communications Co., Ltd.

Research paper thumbnail of Combined Infection Control and Enhanced Osteogenic Differentiation Capacity on Additive Manufactured Ti‐6Al‐4V are Mediated via Titania Nanotube Delivery of Novel Biofilm Inhibitors

Advanced Materials Interfaces, 2020

Additive manufacturing (AM) of titanium alloys offers the capacity to fabricate patient-specific ... more Additive manufacturing (AM) of titanium alloys offers the capacity to fabricate patient-specific implants with defined porous architecture to enhance bone-implant fixation. However, clinical challenges associated with orthopedic implants include inconsistent osseointegration and biofilm-associated peri-implant infection, leading to implant failure. Here, a strategy is developed to reduce infection and promote osteogenesis simultaneously on AM Ti-6Al-4V implants by delivering biofilm inhibitor molecules via titania nanotube surface modification. Electrochemical anodization is performed on polished and as-manufactured Ti-6Al-4V to generate nanotubes, which are utilized for delivery of a novel methylthioadenosine nucleosidase inhibitor (MTANi) that targets MTAN-a key enzyme in bacterial metabolism involved in biofilm formation-thereby offering biofilm inhibition capacity combined with surface nano-topography for promoting osteogenesis. Clinical isolates of staphylococcus cohnii formed firm biofilms on polished and AM Ti-6Al-4V controls whereas modified implants loaded with MTANi inhibit biofilm formation. Anodized AM Ti-6Al-4V nanotube substrates enhance alkaline phosphatase production, bone-specific protein expression (osteocalcin, collagen I) and mineral deposition of human mesenchymal stromal cells (hMSCs), compared to as-manufactured controls. Importantly, no detrimental effects on hMSC proliferation and osteogenic differentiation are observed for MTANi-loaded substrates. Application of novel MTANi and electrochemical anodization offers a promising strategy for titanium alloy implant surface modification.

Research paper thumbnail of Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with improved print fidelity and osteogenic capacity

Bioprinting, 2019

Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with impr... more Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with improved print fidelity and osteogenic capacity, Bioprinting, https://doi.org/10.1016/ j.bprint.2019.e00073. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Orthopaedic osseointegration: Implantology and future directions

Journal of Orthopaedic Research, 2019

Osseointegration (OI) is the direct anchorage of a metal implant into bone, allowing for the conn... more Osseointegration (OI) is the direct anchorage of a metal implant into bone, allowing for the connection of an external prosthesis to the skeleton. Osseointegration was first discovered in the 1960s based on the microscopic analysis of titanium implant placed into host bone. New bone was observed to attach directly to the metal surface. Following clinical investigations into dentistry applications, OI was adapted to treat extremity amputations. These bone anchored implants, which penetrate the skin and soft tissues, eliminate many of the challenges of conventional prosthetic sockets, such as poor fit and suspension, skin breakdown, and pain. Osseointegrated implants show promise to improve prosthesis use, pain, and function for amputees. The successful process of transcutaneous metal integration into host bone requires three synergistic systems: the host bone, the metal implant, and the skin‐implant interface. All three systems must be optimized for successful incorporation and longevity of the implant. Osseointegration begins during surgical implantation of the metal components through a complex interplay of cellular mechanisms. While implants can vary in design—including the original screw, press fit implants, and compressive osseointegration—they face common challenges to successful integration and maintenance of fixation within the host bone. Overcoming these challenges requires the understanding of the complex interactions between each element of OI. This review outlines (a) the basic components of OI, (b) the science behind both the bone‐implant and the skin‐implant interfaces, (c) the current challenges of OI, and (d) future opportunities within the field.

Research paper thumbnail of Hydrodynamic control of titania nanotube formation on Ti-6Al-4V alloys enhances osteogenic differentiation of human mesenchymal stromal cells

Materials Science and Engineering: C, 2020

In order to obtain bioactive bone-implant interfaces with enhanced osteogenic capacity, various a... more In order to obtain bioactive bone-implant interfaces with enhanced osteogenic capacity, various approaches have been developed to modify surface physicochemical properties of bio-inert titanium and titanium alloys. One promising strategy involves fabricating highly ordered nanotubes (NT) on implant surfaces via electrochemical anodization. However, few studies have applied this technique to Ti-6Al-4V alloys most commonly adopted for the fabrication of osteo-integrated surfaces on orthopedic implants. In this study, we investigated the influence of electrolyte hydrodynamics to NT fabrication on Ti-6Al-4V in ethylene glycol based electrolyte and evaluated the osteogenic differentiation capacity of human mesenchymal stromal cells (hMSCs) on different diameter NT surfaces. Computational Fluid Dynamics (CFD) analysis was used to simulate electrolyte flow profiles under various stirring conditions (e.g. stirrer bar location and flow direction) and their correlation to NT formation. Polished Ti-6Al-4V disks (240 grit) were anodized at 20 and 40 V under optimal electrolyte flow conditions for comparison of NT diameter-controlled osteogenic differentiation and mineralization potential of hMSCs over 21 days culture in osteogenic media. Ti-6Al-4V surfaces anodized with 20 and 40 V resulted with NTs diameter approx. 39 and 83 nm, respectively. Electrolyte hydrodynamics (flow profile) significantly influenced the uniformity of NT formation. Here, a uniform velocity and shear stress profile at the surface promoted homogeneous NT growth, whereas large variation in either flow velocity or shear stress to the surface impaired mature NT formation. After 21 days of culture, fluorescence staining demonstrated significantly greater osteocalcin and osteopontin expression, and increased mineralized deposits (xylenol orange staining) on fluctuating NT surfaces anodized under 20 V (Ø 39 nm) relative to flat NT layer anodized with 40 V (Ø 83 nm) and polished controls. This study provides a systematic investigation of NT formation with respect to the electrolyte hydrodynamic effects to NT growth on Ti-6Al-4V alloys, demonstrating the feasibility of a one-step anodization process for generating uniform NT under optimal hydrodynamics. Optimized wavy micro-/nano-topography with Ø 39 nm NT stimulated osteogenic differentiation capacity of hMSCs on Ti-6Al-4V alloys and confirmed the potential application of anodization to improve osteo-integrative surfaces in orthopedic implants.

Research paper thumbnail of Lipid nanoparticle-based formulations for high-performance dentistry applications

Journal of Materials Chemistry B

This review provides a comprehensive discussion on the synthesis and application of different lip... more This review provides a comprehensive discussion on the synthesis and application of different lipid nanoformulations in dentistry while highlighting the challenges and alternative approaches for improved functional efficacy.

Research paper thumbnail of LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research

Journal of Materials Chemistry B

Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and... more Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and surface chemistry to work as a therapeutic delivery agent and a diagnostic tool for non-invasive real-time monitoring using SPCCT imaging technology.

Research paper thumbnail of Biofabrication of Modular Spheroids as Tumor‐Scale Microenvironments for Drug Screening

Advanced Healthcare Materials

Research paper thumbnail of Correction: Lipid nanoparticle-based formulations for high-performance dentistry applications

Journal of Materials Chemistry B

Correction for ‘Lipid nanoparticle-based formulations for high-performance dentistry applications... more Correction for ‘Lipid nanoparticle-based formulations for high-performance dentistry applications’ by Isha Mutreja et al., J. Mater. Chem. B, 2023, https://doi.org/10.1039/D3TB00431G.

Research paper thumbnail of A Novel Dental Polymer with a Flipped External Ester Group Design that Resists Degradation via Polymer Backbone Preservation

Current dental sealants with methacrylate based chemistry are prone to hydrolytic degradation. A ... more Current dental sealants with methacrylate based chemistry are prone to hydrolytic degradation. A conventional ethylene glycol dimethacrylate (EGDMA) was compared to a novel methacrylate monomer with a flipped external ester group (ethylene glycol ethyl methacrylate-EGEMA) that was designed to resist polymer degradation effects. Fourier transform infrared spectroscopy and water contact angle confirmed a comparable degree of initial conversion and surface wettability for EGDMA and EGEMA. EGDMA disks initially performed better compared to EGEMA as suggested by higher surface hardness and 1.5 times higher diametral tensile strength (DTS). After 15 weeks of hydrolytic and accelerated aging, EGDMA and EGEMA DTS was reduced by 88% and 44% respectively. This accelerated aging model resulted in 3.3 times higher water sorption for EDGMA than EGEMA disks. EGDMA had an increase in grain boundary defects and visible erosion sites with accelerated aging, while for EGEMA the changes were not significant.

Research paper thumbnail of Gelatin Methacryloyl Hydrogels for Musculoskeletal Tissue Regeneration

Bioengineering

Musculoskeletal disorders are a significant burden on the global economy and public health. Hydro... more Musculoskeletal disorders are a significant burden on the global economy and public health. Hydrogels have significant potential for enhancing the repair of damaged and injured musculoskeletal tissues as cell or drug delivery systems. Hydrogels have unique physicochemical properties which make them promising platforms for controlling cell functions. Gelatin methacryloyl (GelMA) hydrogel in particular has been extensively investigated as a promising biomaterial due to its tuneable and beneficial properties and has been widely used in different biomedical applications. In this review, a detailed overview of GelMA synthesis, hydrogel design and applications in regenerative medicine is provided. After summarising recent progress in hydrogels more broadly, we highlight recent advances of GelMA hydrogels in the emerging fields of musculoskeletal drug delivery, involving therapeutic drugs (e.g., growth factors, antimicrobial molecules, immunomodulatory drugs and cells), delivery approaches...

Research paper thumbnail of Methacrylate Polymers With “Flipped External” Ester Groups: A Review

Frontiers in Dental Medicine

Current resin composites have favorable handling and upon polymerization initial physical propert... more Current resin composites have favorable handling and upon polymerization initial physical properties that allow for efficient material replacement of removed carious tooth structure. Dental resin composites have long term durability limitations due to the hydrolysis of ester bonds within the methacrylate based polymer matrix. This article outlines the importance of ester bonds positioned internal to the carbon-carbon double bond in current methacrylate monomers. Water and promiscuous salivary/bacterial esterase activity can initiate ester bond hydrolysis that can sever the polymer backbone throughout the material. Recent studies have custom synthesized, with the latest advances in modern organic chemical synthesis, a novel molecule named ethylene glycol bis (ethyl methacrylate) (EGEMA). EGEMA was designed to retain the reactive acrylate units. Upon intermolecular polymerization of vinyl groups, EGEMA ester groups are positioned outside the backbone of the polymer chain. This review ...

Research paper thumbnail of Hybrid nanocoatings of self-assembled organic-inorganic amphiphiles for prevention of implant infections

Acta Biomaterialia, 2022

Antimicrobial coatings are one of the most promising strategies to prevent bacterial infections i... more Antimicrobial coatings are one of the most promising strategies to prevent bacterial infections in orthopedic and dental implants. Combining antimicrobial agents with different antimicrobial mechanisms might have synergistic effects and be more potent. Others have shown that nanocomposites of silver nanoparticles (AgNPs) decorated with antimicrobial peptides (AMPs) show increased potency as free agents in solution. However, similar nanocomposites have not been explored to coat biomaterials through cooperative weak electrostatic attraction forces between AMP, AgNPs and substrates in need of protection against infection. In this work, we synthesized self-assembled antimicrobial amphiphiles of an AMP, GL13K. Then, we decorated the AMP nanostructures with AgNPs, which were finally used to coat etched Ti (eTi) surfaces. The strong hydrogen bonding between the AMP amphiphiles and the polar eTi yielded a robust and stable coating. When compared to single AgNP or single AMP coatings, our hybrid nanocoatings had notably higher in vitro antimicrobial potency against multiple bacteria strains related to implant infection. The hybrid coating also showed relevant antimicrobial activity in an in vivo subcutaneous infection model in rats. This work advances the application of AgNP/AMP nanocomposites as effective coatings for prevention of implant infections. STATEMENT OF SIGNIFICANCE: : High morbidity, mortality and elevated costs are associated with orthopedic and dental implant infections. Conventional antibiotic treatment is ineffective due to barrier-like extracellular polysaccharide substances in biofilms and the increasing threat from antibiotic resistance. Antimicrobial coatings are one of the most promising strategies, but the performance is usually unsatisfactory, especially when tested in vivo. Here, we present a hybrid nanocoating with different modes of action to prevent implant infections using self-assembled antimicrobial peptide (AMP) amphiphiles decorated with silver nanoparticles (AgNPs). When compared to single AgNP or AMP coatings, our hybrid nanocoatings showed significant increases in antimicrobial potency against multiple implant infection-related bacterial strains in vitro and in an in vivo rat subcutaneous infection model.

Research paper thumbnail of Culture and characterization of various porcine integumentary-connective tissue-derived mesenchymal stromal cells to facilitate tissue adhesion to percutaneous metal implants

Stem Cell Research & Therapy, 2021

Background Transdermal osseointegrated prosthesis have relatively high infection rates leading to... more Background Transdermal osseointegrated prosthesis have relatively high infection rates leading to implant revision or failure. A principle cause for this complication is the absence of a durable impervious biomechanical seal at the interface of the hard structure (implant) and adjacent soft tissues. This study explores the possibility of recapitulating an analogous cellular musculoskeletal-connective tissue interface, which is present at naturally occurring integumentary tissues where a hard structure exits the skin, such as the nail bed, hoof, and tooth. Methods Porcine mesenchymal stromal cells (pMSCs) were derived from nine different porcine integumentary and connective tissues: hoof-associated superficial flexor tendon, molar-associated periodontal ligament, Achilles tendon, adipose tissue and skin dermis from the hind limb and abdominal regions, bone marrow and muscle. For all nine pMSCs, the phenotype, multi-lineage differentiation potential and their adhesiveness to clinical ...

Research paper thumbnail of Utilizing a degradation prediction pathway system to understand how a novel methacrylate derivative polymer with flipped external ester groups retains physico-mechanical properties following esterase exposure

Dental Materials, 2021

The region of failure for current methacrylates (i.e. derivatives of acrylates) are ester bond li... more The region of failure for current methacrylates (i.e. derivatives of acrylates) are ester bond linkages that hydrolyze in the presence of salivary and bacterial esterases that break the polymer network backbone. This effect decreases the mechanical properties of methacrylate-based materials. The ethylene glycol dimethacrylate (EGDMA) or novel ethylene glycol ethyl methacrylate (EGEMA) discs were prepared using 40 µL of the curing mixture containing photo/co-initiators for 40 s in a PTFE mold at 1000 mW/cm2. The degree of conversion was used as a quality control measure for the prepared discs, followed by physical, mechanical, and chemical characterization of discs properties before and after cholesterol esterase treatment. After 9 weeks of standardized cholesterol esterase (CEase) exposure, EGDMA discs showed exponential loss of material (p = 0.0296), strength (p = 0.0014) and increased water sorption (p = 0.0002) compared to EGEMA discs. We integrated a degradation prediction pathway system to LC/MS and GC/MS analyses to elucidate the degradation by-products of both EGEMA and EGDMA polymers. GC/MS analysis demonstrated that the esterase catalysis was directed to central polymer backbone breakage, producing ethylene glycol, for EGDMA, and to side chain breakage, producing ethanol, for EGEMA. The flipped external ester group linkage design is attributed to EGEMA showing higher resistance to esterase biodegradation and changes in mechanical and physical properties than EGDMA. EGEMA is a potential substitute for common macromer diluents, such as EGDMA, based on its resistance to biodegradation effects. This work inspires the flipped external group design to be applied to analogs of current larger, hydrophobic strength bearing macromers used in future dental material formulations.

Research paper thumbnail of Response of osteoblast cells to titanium and hydroxyapatite sputter deposited polystyrene

Research paper thumbnail of A novel methacrylate derivative polymer that resists bacterial cell‐mediated biodegradation

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2021

This study tests biodegradation resistance of a custom synthesized novel ethylene glycol ethyl me... more This study tests biodegradation resistance of a custom synthesized novel ethylene glycol ethyl methacrylate (EGEMA) with ester bond linkages that are external to the central polymer backbone when polymerized. Ethylene glycol dimethacrylate (EGDMA) with internal ester bond linkages and EGEMA discs were prepared in a polytetrafluoroethylene (PTFE) mold using 40 μl macromer and photo/co-initiator mixture cured for 40 s at 1000 mW/cm2 . The discs were stored in the constant presence of Streptococcus mutans (S. mutans) in Todd Hewitt Yeast + Glucose (THYE+G) media up to 9 weeks (n = 8 for each macromer type) and physical/mechanical properties were assessed. Initial measurements EGEMA versus EGDMA polymer discs showed equivalent degree of conversion (45.69% ± 2.38 vs. 46.79% ± 4.64), diametral tensile stress (DTS; 8.12± 2.92 MPa vs. 6.02 ± 1.48 MPa), and low subsurface optical defects (0.41% ± 0.254% vs. 0.11% ± 0.074%). The initial surface wettability (contact angle) was slightly higher (p ≤ .012) for EGEMA (62.02° ± 3.56) than EGDMA (53.86° ± 5.61°). EGDMA showed higher initial Vicker's hardness than EGEMA (8.03 ± 0.88 HV vs. 5.93 ± 0.69 HV; p ≤ .001). After 9 weeks of S. mutans exposure, EGEMA (ΔDTS-1.30 MPa) showed higher resistance to biodegradation effects with a superior DTS than EGDMA (ΔDTS-6.39 MPa) (p = .0039). Visible and scanning electron microscopy images of EGEMA show less surface cracking and defects than EGDMA. EGDMA had higher loss of material (18.9% vs. 8.5%, p = .0009), relative changes to fracture toughness (92.5% vs. 49.2%, p = .0022) and increased water sorption (6.1% vs. 1.9%, p = .0022) compared to EGEMA discs. The flipped external ester group linkage design is attributed to EGEMA showing higher resistance to bacterial degradation effects than an internal ester group linkage design methacrylate.

Research paper thumbnail of Micro- and Nanopatterning of Freestanding Protein Films

Biodegradable casein films have significant potential for use as non-supported stand-alone sheeti... more Biodegradable casein films have significant potential for use as non-supported stand-alone sheeting in orthopaedic implants and tissue engineering substrates. Multi-scale surface patterns can be used to modulate and guide cell interaction by means of an engineered construct. The majority of work on cell-pattern interaction has so far focused on non-degradable materials. In this paper we demonstrate for the first time the fabrication of microand nano-scale geometric patterns on the surface of a crosslinked biodegradable casein film. To achieve this we introduce a two-step fabrication procedure based on polydimethylsiloxane (PDMS) softlithography. We will show the reproduction of microand nanoscale patterns in liquid-cast casein films. We also demonstrate film formation and cross-linking using glutaraldehyde and discuss the use of these films as cell-culture substrates.

Research paper thumbnail of Cell responses to titanium and titanium alloys

Commercially pure titanium and titanium alloys have been extensively used for designing musculosk... more Commercially pure titanium and titanium alloys have been extensively used for designing musculoskeletal implants due to their biocompatibility and mechanical properties. The clinical success of these implants relies on supporting favorable osteoimmune environment, which then regulates bone regeneration and evades bacterial infection. Several surface engineering strategies have been employed to impart multifunctional properties to the otherwise bioinert titanium and titanium alloys. This chapter outlines these strategies, which encompass physical and chemical modification and their downstream effects on cell responses. In particular, we introduce the effect of these modifications on cells from hard and soft tissue along with their antibacterial properties and immune-modulatory effects. This chapter provides an up-to-date summary of where we are and how the understanding of the cellular response in vitro can help up drive the implant design for effective tissue repair and regeneration...

Research paper thumbnail of Hybrid biofabrication of 3D osteoconductive constructs comprising Mg-based nanocomposites and cell-laden bioinks for bone repair

Bone, 2021

Tissue engineering approaches for bone repair have rapidly evolved due to the development of nove... more Tissue engineering approaches for bone repair have rapidly evolved due to the development of novel biofabrication technologies, providing an opportunity to fabricate anatomically-accurate living implants with precise placement of specific cell types. However, limited availability of biomaterial inks, that can be 3D-printed with high resolution, while providing high structural support and the potential to direct cell differentiation and maturation towards the osteogenic phenotype, remains an ongoing challenge. Aiming towards a multifunctional biomaterial ink with high physical stability and biological functionality, this work describes the development of a nanocomposite biomaterial ink (Mg-PCL) comprising of magnesium hydroxide nanoparticles (Mg) and polycaprolactone (PCL) thermoplastic for 3D printing of strong and bioactive bone regenerative scaffolds. We characterised the Mg nanoparticle system and systematically investigated the cytotoxic and osteogenic effects of Mg supplementation to human mesenchymal stromal cells (hMSCs) 2D-cultures. Next, we prepared Mg-PCL biomaterial ink using a solvent casting method, and studied the effect of Mg over mechanical properties, printability and scaffold degradation. Furthermore, we delivered MSCs within Mg-PCL scaffolds using a gelatin-methacryloyl (GelMA) matrix, and evaluated the effect of Mg over cell viability and osteogenic differentiation. Nanocomposite Mg-PCL could be printed with high fidelity at 20 wt% of Mg content, and generated a mechanical reinforcement between 30%-400% depending on the construct internal geometry. We show that Mg-PCL degrades faster than standard PCL in an accelerated-degradation assay, which has positive implications towards in vivo implant degradation and bone regeneration. Mg-PCL did not affect MSCs viability, but enhanced osteogenic differentiation and bone-specific matrix deposition, as demonstrated by higher ALP/DNA levels and Alizarin Red calcium staining. Finally, we present proof of concept of Mg-PCL being utilised in combination with a bone-specific bioink (Sr-GelMA) in a coordinated-extrusion bioprinting strategy for fabrication of hybrid constructs with high stability and synergistic biological functionality. Mg-PCL further enhanced the osteogenic differentiation of encapsulated MSCs and supported bone ECM deposition within the bioink component of the hybrid construct, evidenced by mineralised nodule formation, osteocalcin (OCN) and collagen type-I (Col I) expression within the bioink filaments. This study demonstrated that magnesium-based nanocomposite bioink material optimised for extrusion-based 3D printing of bone regenerative scaffolds provide enhanced mechanical stability and bone-related bioactivity with promising potential for skeletal tissue regeneration.

Research paper thumbnail of Biomimetic mineralized hybrid scaffolds with antimicrobial peptides

Bioactive Materials, 2021

Infection in hard tissue regeneration is a clinically-relevant challenge. Development of scaffold... more Infection in hard tissue regeneration is a clinically-relevant challenge. Development of scaffolds with dual function for promoting bone/dental tissue growth and preventing bacterial infections is a critical need in the field. Here we fabricated hybrid scaffolds by intrafibrillar-mineralization of collagen using a biomimetic process and subsequently coating the scaffold with an antimicrobial designer peptide with cationic and amphipathic properties. The highly hydrophilic mineralized collagen scaffolds provided an ideal substrate to form a dense and stable coating of the antimicrobial peptides. The amount of hydroxyapatite in the mineralized fibers modulated the rheological behavior of the scaffolds with no influence on the amount of recruited peptides and the resulting increase in hydrophobicity. The developed scaffolds were potent by contact killing of Gram-negative Escherichia coli and Gram-positive Streptococcus gordonii as well as cytocompatible to human bone marrow-derived mesenchymal stromal cells. The process of scaffold fabrication is versatile and can be used to control mineral load and/ or intrafibrillar-mineralized scaffolds made of other biopolymers. Peer review under responsibility of KeAi Communications Co., Ltd.

Research paper thumbnail of Combined Infection Control and Enhanced Osteogenic Differentiation Capacity on Additive Manufactured Ti‐6Al‐4V are Mediated via Titania Nanotube Delivery of Novel Biofilm Inhibitors

Advanced Materials Interfaces, 2020

Additive manufacturing (AM) of titanium alloys offers the capacity to fabricate patient-specific ... more Additive manufacturing (AM) of titanium alloys offers the capacity to fabricate patient-specific implants with defined porous architecture to enhance bone-implant fixation. However, clinical challenges associated with orthopedic implants include inconsistent osseointegration and biofilm-associated peri-implant infection, leading to implant failure. Here, a strategy is developed to reduce infection and promote osteogenesis simultaneously on AM Ti-6Al-4V implants by delivering biofilm inhibitor molecules via titania nanotube surface modification. Electrochemical anodization is performed on polished and as-manufactured Ti-6Al-4V to generate nanotubes, which are utilized for delivery of a novel methylthioadenosine nucleosidase inhibitor (MTANi) that targets MTAN-a key enzyme in bacterial metabolism involved in biofilm formation-thereby offering biofilm inhibition capacity combined with surface nano-topography for promoting osteogenesis. Clinical isolates of staphylococcus cohnii formed firm biofilms on polished and AM Ti-6Al-4V controls whereas modified implants loaded with MTANi inhibit biofilm formation. Anodized AM Ti-6Al-4V nanotube substrates enhance alkaline phosphatase production, bone-specific protein expression (osteocalcin, collagen I) and mineral deposition of human mesenchymal stromal cells (hMSCs), compared to as-manufactured controls. Importantly, no detrimental effects on hMSC proliferation and osteogenic differentiation are observed for MTANi-loaded substrates. Application of novel MTANi and electrochemical anodization offers a promising strategy for titanium alloy implant surface modification.

Research paper thumbnail of Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with improved print fidelity and osteogenic capacity

Bioprinting, 2019

Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with impr... more Design and characterisation of multi-functional strontium-gelatin nanocomposite bioinks with improved print fidelity and osteogenic capacity, Bioprinting, https://doi.org/10.1016/ j.bprint.2019.e00073. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Orthopaedic osseointegration: Implantology and future directions

Journal of Orthopaedic Research, 2019

Osseointegration (OI) is the direct anchorage of a metal implant into bone, allowing for the conn... more Osseointegration (OI) is the direct anchorage of a metal implant into bone, allowing for the connection of an external prosthesis to the skeleton. Osseointegration was first discovered in the 1960s based on the microscopic analysis of titanium implant placed into host bone. New bone was observed to attach directly to the metal surface. Following clinical investigations into dentistry applications, OI was adapted to treat extremity amputations. These bone anchored implants, which penetrate the skin and soft tissues, eliminate many of the challenges of conventional prosthetic sockets, such as poor fit and suspension, skin breakdown, and pain. Osseointegrated implants show promise to improve prosthesis use, pain, and function for amputees. The successful process of transcutaneous metal integration into host bone requires three synergistic systems: the host bone, the metal implant, and the skin‐implant interface. All three systems must be optimized for successful incorporation and longevity of the implant. Osseointegration begins during surgical implantation of the metal components through a complex interplay of cellular mechanisms. While implants can vary in design—including the original screw, press fit implants, and compressive osseointegration—they face common challenges to successful integration and maintenance of fixation within the host bone. Overcoming these challenges requires the understanding of the complex interactions between each element of OI. This review outlines (a) the basic components of OI, (b) the science behind both the bone‐implant and the skin‐implant interfaces, (c) the current challenges of OI, and (d) future opportunities within the field.

Research paper thumbnail of Hydrodynamic control of titania nanotube formation on Ti-6Al-4V alloys enhances osteogenic differentiation of human mesenchymal stromal cells

Materials Science and Engineering: C, 2020

In order to obtain bioactive bone-implant interfaces with enhanced osteogenic capacity, various a... more In order to obtain bioactive bone-implant interfaces with enhanced osteogenic capacity, various approaches have been developed to modify surface physicochemical properties of bio-inert titanium and titanium alloys. One promising strategy involves fabricating highly ordered nanotubes (NT) on implant surfaces via electrochemical anodization. However, few studies have applied this technique to Ti-6Al-4V alloys most commonly adopted for the fabrication of osteo-integrated surfaces on orthopedic implants. In this study, we investigated the influence of electrolyte hydrodynamics to NT fabrication on Ti-6Al-4V in ethylene glycol based electrolyte and evaluated the osteogenic differentiation capacity of human mesenchymal stromal cells (hMSCs) on different diameter NT surfaces. Computational Fluid Dynamics (CFD) analysis was used to simulate electrolyte flow profiles under various stirring conditions (e.g. stirrer bar location and flow direction) and their correlation to NT formation. Polished Ti-6Al-4V disks (240 grit) were anodized at 20 and 40 V under optimal electrolyte flow conditions for comparison of NT diameter-controlled osteogenic differentiation and mineralization potential of hMSCs over 21 days culture in osteogenic media. Ti-6Al-4V surfaces anodized with 20 and 40 V resulted with NTs diameter approx. 39 and 83 nm, respectively. Electrolyte hydrodynamics (flow profile) significantly influenced the uniformity of NT formation. Here, a uniform velocity and shear stress profile at the surface promoted homogeneous NT growth, whereas large variation in either flow velocity or shear stress to the surface impaired mature NT formation. After 21 days of culture, fluorescence staining demonstrated significantly greater osteocalcin and osteopontin expression, and increased mineralized deposits (xylenol orange staining) on fluctuating NT surfaces anodized under 20 V (Ø 39 nm) relative to flat NT layer anodized with 40 V (Ø 83 nm) and polished controls. This study provides a systematic investigation of NT formation with respect to the electrolyte hydrodynamic effects to NT growth on Ti-6Al-4V alloys, demonstrating the feasibility of a one-step anodization process for generating uniform NT under optimal hydrodynamics. Optimized wavy micro-/nano-topography with Ø 39 nm NT stimulated osteogenic differentiation capacity of hMSCs on Ti-6Al-4V alloys and confirmed the potential application of anodization to improve osteo-integrative surfaces in orthopedic implants.