Teaching Medical Devices through Interactive Innovation: Challenges and Rewards.

Medical devices are manmade objects existing at the interface between numerous disciplines. They range from as simple as medical gloves to as complex as artificial limbs. This versatility of medical devices and their inherent interdisciplinary nature means that academic courses on them are attended by cohorts of students from varieties of academic backgrounds, who bring with them similarly broad spectra of interests. To satisfy the learning expectations of each and every student in such diverse classes is a daunting task for the instructor. After many years of teaching medical devices at undergraduate and graduate levels at three different universities in the states of Illinois and California, I have come up with an instructional method that solves this challenge by engaging students in the co-creation of the curriculum via selection of their own medical devices of interest and presentation to the class for collective analysis. The threefold presentations are designed so that they reflect an ascent along the hierarchy of a learning taxonomy extending from foundational concepts to critical assessment of knowledge to creative displays of it. In such a way, the students are acquainted with the ability of critical and creative thinking at the expense of rote memorization or inculcation and are prepared to enter the field of medical devices as innovation-centered individuals. The specifics of this new method of instruction are reported here, with the hope that they will be useful to fellow instructors in any interdisciplinary course that benefits from a balance between the rigorous coverage of the instructional material pertaining to engineering and medicine and the flexible selection of topics that comply with students' individual interests.

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Bacterial cellulose (BC) is a type of extracellular polymeric nanomaterial secreted by microorganisms over the course of their growth. It has gained significant attention in the field of bone tissue engineering due to its unique structure of three-dimensional fibrous network, excellent biocompatibility, biodegradability, and exceptional mechanical properties. Nevertheless, BC still has some weaknesses, including low osteogenic activity, a lack of antimicrobial properties, small pore size, issues with the degradation rate, and a mismatch in bone tissue regeneration, limiting its standalone use in the field of bone tissue engineering. Therefore, the modification of BC and the preparation of BC composite materials have become a recent research focus. Herein, we summarized the relationships between the production, modification, and bone repair applications of BC. We introduced the methods for the preparation and the modification of BC. Additionally, we elaborated on the new advances in the application of BC composite materials in the field of bone tissue engineering. We also highlighted the existing challenges and future prospects of BC composite materials.

Stimulus-Responsive Amino Acids Behind In Situ Assembled Bioactive Peptide Materials.

In situ self-assembly of peptides into well-defined nanostructures represents one of versatile strategies for creation of bioactive materials within living cells with great potential in disease diagnosis and treatment. The intimate relationship between amino acid sequences and the assembling propensity of peptides has been thoroughly elucidated over the past few decades. This has inspired development of various controllable self-assembling peptide systems based on stimuli-responsive naturally occurring or non-canonical amino acids, including redox-, pH-, photo-, enzyme-responsive amino acids. This review attempts to summarize the recent progress achieved in manipulating in situ self-assembly of peptides by controllable reactions occurring to amino acids. We will highlight the systems containing non-canonical amino acids developed in our laboratory during the past few years, primarily including acid/enzyme-responsive 4-aminoproline, redox-responsive (seleno)methionine, and enzyme-responsive 2-nitroimidazolyl alanine. Utilization of the stimuli-responsive assembling systems in creation of bioactive materials will be specifically introduced to emphasize their advantages for addressing the concerns lying in disease theranostics. Eventually, we will provide the perspectives for the further development of stimulus-responsive amino acids and thereby demonstrating their great potential in development of next-generation biomaterials.

Application of biomedical materials in the diagnosis and treatment of myocardial infarction.

Myocardial infarction (MI) is a cardiovascular emergency and the leading cause of death worldwide. Inflammatory and immune responses are initiated immediately after MI, leading to myocardial death, scarring, and ventricular remodeling. Current therapeutic approaches emphasize early restoration of ischemic myocardial reperfusion, but there is no effective treatment for the pathological changes of infarction. Biomedical materials development has brought new hope for MI diagnosis and treatment. Biomedical materials, such as cardiac patches, hydrogels, nano biomaterials, and artificial blood vessels, have played an irreplaceable role in MI diagnosis and treatment. They improve the accuracy and efficacy of MI diagnosis and offer further possibilities for reducing inflammation, immunomodulation, inhibiting fibrosis, and cardiac regeneration. This review focuses on the advances in biomedical materials applications in MI diagnosis and treatment. The current studies are outlined in terms of mechanisms of action and effects. It is addressed how biomedical materials application can lessen myocardial damage, encourage angiogenesis, and enhance heart function. Their clinical transformation value and application prospect are discussed.

Angio-osteogenic capacity of octacalcium phosphate co-precipitated with copper gluconate in rat calvaria critical-sized defect.

The objective of this study is to investigate the effects of octacalcium phosphate (OCP)-induced bone regeneration on angiogenesis regulated by the inclusion of copper ions in OCP in vitro and in vivo. Calcium (Ca)-deficient Cu-OCPs, containing 0.01 wt% Cu (low-Cu-OCP) and 0.12 wt% Cu (high-Cu-OCP), were synthesized with co7pper gluconate salt. The lattice parameters of Cu-OCPs tended to decrease slightly with Cu inclusion, as estimated by Rietveld analysis. Cu ions were released in OCP when the materials were incubated in the medium for human umbilical vein endothelial cells (HUVECs). The solubility of Cu-OCPs, estimated by the degree of supersaturation, was slightly higher than that of the original OCP. Cu-OCP tended to hydrolyze to an apatite structure while maintaining the crystal plate-like morphology when incubated with mesenchymal stem D1 cells in osteogenic media for 14 days. The specimens were characterized by selected area electron diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. Low-Cu-OCP significantly enhanced the HUVEC capillary cross-linking density. D1 cell differentiation was inhibited with the inclusion of Cu, even at low concentrations. The composite of low-Cu-OCP with a gelatin sponge (low-Cu-OCP/Gel) significantly enhanced angiogenesis coupled with bone regeneration when implanted in a rat calvarial critical-sized defect for 4 weeks, compared with the corresponding amount of Cu-containing Gel (Cu/Gel) or OCP/Gel materials through angiography and tissue histomorphometry. These results support the proposition that angiogenesis stimulated by low-Cu-OCP is closely related with enhanced bone regeneration.

Laser-Induced Graphene for Heartbeat Monitoring with HeartPy Analysis.

The HeartPy Python toolkit for analysis of noisy signals from heart rate measurements is an excellent tool to use in conjunction with novel wearable sensors. Nevertheless, most of the work to date has focused on applying the toolkit to data measured with commercially available sensors. We demonstrate the application of the HeartPy functions to data obtained with a novel graphene-based heartbeat sensor. We produce the sensor by laser-inducing graphene on a flexible polyimide substrate. Both graphene on the polyimide substrate and graphene transferred onto a PDMS substrate show piezoresistive behavior that can be utilized to measure human heartbeat by registering median cubital vein motion during blood pumping. We process electrical resistance data from the graphene sensor using HeartPy and demonstrate extraction of several heartbeat parameters, in agreement with measurements taken with independent reference sensors. We compare the quality of the heartbeat signal from graphene on different substrates, demonstrating that in all cases the device yields results consistent with reference sensors. Our work is a first demonstration of successful application of HeartPy to analysis of data from a sensor in development.

A Diels-Alder polymer platform for thermally enhanced drug release toward efficient local cancer chemotherapy.

We reports a novel thermally enhanced drug release system synthesized via a dynamic Diels-Alder (DA) reaction to develop chemotherapy for pancreatic cancer. The anticancer prodrug was designed by tethering gemcitabine (GEM) to poly(furfuryl methacrylate) (PFMA) via N-(3-maleimidopropionyloxy)succinimide as a linker by DA reaction (PFMA-L-GEM). The conversion rate of the DA reaction was found to be approximately 60% at room temperature for 120 h. The reversible deconstruction of the DA covalent bond in retro Diels-Alder (rDA) reaction was confirmed by proton nuclear magnetic resonance, and the reaction was significantly accelerated at 90 °C. A PFMA-LGEM film containing magnetic nanoparticles (MNPs) was prepared for thermally enhanced release of the drug via the rDA reaction. Drug release was initiated by heating MNPs by alternating magnetic field. This enables local heating within the film above the rDA reaction temperature while maintaining a constant surrounding medium temperature. The MNPs/PFMA-L-GEM film decreased the viability of pancreatic cancer cells by 49% over 24 h. Our results suggest that DA/rDA-based thermally enhanced drug release systems can serve as a local drug release platform and deliver the target drug within locally heated tissue, thereby improving the therapeutic efficiency and overcoming the side effects of conventional drugs used to treat pancreatic cancer.

Bioresorbable porous ß-tricalcium phosphate chelate-setting cements with poly(lactic-co-glycolic acid) particles as pore-forming agent: fabrication, material properties, cytotoxicity, and in vivo evaluation.

Calcium-phosphate cements (CPCs) have been used as bone filling materials in orthopaedic surgery. However, CPCs are set using an acid-base reaction, and then change into stable hydroxyapatite (HAp) in a living body. Therefore, we developed bioresorbable chelate-setting ß-tricalcium phosphate (ß-TCP) cements based on surface modifications of inositol phosphate (IP6). In order to improve the bioresorbability, we fabricated IP6/ß-TCP cements hybridized with poly(lactic-co-glycolic acid) (PLGA) particles as a pore-forming agent. The compressive strengths of the cements with the amounts of 5 and 10 mass% PLGA particles were 23.2 and 22.8 MPa, respectively. There was no significant difference from cements without PLGA (23.4 MPa). The setting times of the cement specimens with PLGA particles (30 min) were a little longer than those without PLGA particles (26.3 min). The lack of cytotoxicity of the cement specimens was confirmed using osteoblast-like cells (MC3T3-E1). Cylindrical defects were made by drilling into the tibia of mini-pigs and injecting the prepared cement pastes into the defects. Twelve weeks after implantation the specimens were stained with toluidine blue and histologically evaluated. Histological evaluation of cement specimens with PLGA particles showed enhanced bioresorbability. Newly-formed bone was also observed inside cement specimens with PLGA particles. The IP6/ß-TCP cement specimens with PLGA particles had excellent material properties, such as injectability, compressive strength, high porosity, no cytotoxicity in vitro, bioresorption and bone formation abilities in vivo. Organic-inorganic hybridized CPCs are expected to be valuable as novel biodegradable paste-like artificial bone fillers.

Magnetic stimulation of the angiogenic potential of mesenchymal stromal cells in vascular tissue engineering.

The growing prevalence of vascular diseases worldwide has emphasized the need for novel tissue-engineered options concerning the development of vascularized 3D constructs. This study reports, for the first time, the use of external magnetic fields to stimulate mesenchymal stromal cells (MSCs) to increase the production of vascular endothelial growth factor-A (VEGF-A). Polyvinylalcohol and gelatin-based scaffolds, containing iron oxide nanoparticles, were designed for optimal cell magnetic stimulation. While the application of static magnetic fields over 24 h did not impact on MSCs proliferation, viability and phenotypic identity, it significantly increased the production of VEGF-A and guided MSCs morphology and alignment. The ability to enhance MSCs angiogenic potential was demonstrated by the increase in the number of new vessels formed in the presence of MSCs conditioned media through in vitro and in vivo models. Ultimately, this study uncovers the potential to manipulate cellular processes through short-term magnetic stimulation.

Controlled biointerfaces with biomimetic phosphorus-containing polymers.

Phosphorus is a ubiquitous and one of the most common elements found in living organisms. Almost all molecules containing phosphorus in our body exist as analogs of phosphate salts or phosphoesters. Their functions are versatile and important, being responsible for forming the genetic code, cell membrane, and mineral components of hard tissue. Several materials inspired from these phosphorus-containing biomolecules have been recently developed. These materials have shown unique properties at the biointerface, such as nonfouling ability, blood compatibility, lubricity, mineralization induction capability, and bone affinity. Several unfavorable events occur at the interface of materials and living organisms because most of these materials have not been designed while taking host responses into account. These unfavorable events are directly linked to reducing functions and shorten the usable periods of medical devices. Biomimetic phosphorus-containing polymers can improve the reliability of materials in biological systems. In addition, phosphorus-containing biomimetic polymers are useful not only for improving the biocompatibility of material surfaces but also for adding new functions due to the flexibility in molecular design. In this review, we describe the recent advances in the control of biointerfacial phenomena with phosphorus-containing polymers. We especially focus on zwitterioninc phosphorylcholine polymers and polyphosphoesters.

Mutual chemical effect of autograft and octacalcium phosphate implantation on enhancing intramembranous bone regeneration.

This study examined the effect of a mixture of octacalcium phosphate (OCP) and autologous bone on bone regeneration in rat calvaria critical-sized defect (CSD). Mechanically mixed OCP and autologous bone granules (OCP+Auto), approximately 500 to 1000 µm in diameter, and each individual material were implanted in rat CSD for 8 weeks, and subjected to X-ray micro-computed tomography (micro-CT), histology, tartrate-resistant acid phosphatase (TRAP) staining, and histomorphometry for bone regeneration. Osteoblastic differentiation from mesenchymal stem cells (D1 cells) was examined in the presence of non-contacting materials by alkaline phosphatase (ALP) activity for 21 days. The material properties and medium composition before and after the incubation were determined by selected area electron diffraction (SAED) under transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), and chemical analysis. The results showed that while bone formation coupled with TRAP-positive osteoclastic resorption and cellular ALP activity were the highest in the Auto group, a positive effect per OCP weight or per autologous bone weight on ALP activity was found. Although the OCP structure was maintained even after the incubation (SAED), micro-deposits were grown on OCP surfaces (TEM). Fibrous tissue was also exposed on the autologous bone surfaces (SEM). Through FT-IR absorption, it was determined that bone mineral-like characteristics of the phosphate group increased in the OCP + Auto group. These findings were interpreted as a structural change from OCP to the apatitic phase, a conclusion supported by the medium degree of saturation changes. The results demonstrate the mutual chemical effect of mixing OCP with autologous bone as an active bone substitute material.

Cellular therapy for myocardial ischemia using a temperature-responsive biodegradable injectable polymer system with adipose-derived stem cells.

Adipose-derived stem cell (AdSC) has been attracting attention as a convenient stem cell source. Not only AdSC can differentiate into various tissue cells, but it can also accelerate cell proliferation, anti-inflammation, and angiogenesis by secreting paracrine factors. Studies have demonstrated AdSC treatment of ischemic heart. However, an improvement in the remaining live AdSCs administered at the injected site while maintaining paracrine factor secretion is desired to achieve effective regenerative medicine. We previously reported the ABA-type tri-block copolymer of poly(ɛ-caprolactone-co-glycolic acid) and poly(ethylene glycol) (tri-PCG), exhibiting temperature-responsive sol-to-gel transition as biodegradable injectable polymer (IP) systems. Moreover, we recently reported that the biodegradable temperature-triggered chemically cross-linked gelation systems exhibited longer gel state durations using tri-PCG attaching acryloyl groups and a polythiol derivative. In this study, we explored this IP-mediated AdSC delivery system. We investigated the cell viability, mRNA expression, and cytokine secretion of AdSCs cultured in the physical or chemical IP hydrogels. Both of these IP hydrogels retained a certain number of viable cells, and RT-PCR and ELISA analyses revealed that mRNA expression and secretion of vascular endothelial growth factor of the AdSCs cultured in the chemical hydrogel were higher than the physical hydrogel. Moreover, AdSCs injected with the chemical hydrogel into ischemic heart model mice showed longer retention of the cells at the injected site and recovery from the ischemic condition. The results mean that the IP system is a promising candidate for a stem cell delivery system that exhibits the recovery of cardiac function for myocardial infarction treatment.

Tumor growth suppression by implantation of an anti-CD25 antibody-immobilized material near the tumor via regulatory T cell capture.

In this study, we designed and synthesized an implantable anti-CD25 antibody-immobilized polyethylene (CD25-PE) mesh to suppress tumor growth by removing regulatory T cells (Tregs). The PE mesh was graft-polymerized with poly(acrylic acid), and the anti-mouse CD25 antibody was then immobilized using the 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide reaction. Immobilization of the antibody on the PE mesh was confirmed by immunostaining. The CD25-PE mesh could effectively and selectively capture CD25-positive cells through antigen-antibody interactions when the CD25-PE mesh was incubated with a suspension of mouse spleen cells, including CD25-positive cells. In addition, implantation of the CD25-PE mesh into mice subcutaneously demonstrated the Treg-capturing ability of the CD25-PE mesh with only a weak inflammatory reaction. In tumor-bearing mice, tumor growth was suppressed by subcutaneous implantation of the CD25-PE mesh near the tumor for 1 week. These results suggested that the anti-CD25 antibody-immobilized material could capture Tregs in vivo and inhibit tumor proliferation in a limited tumor-bearing mouse model. Further research is needed to facilitate cancer immunotherapy using implantable anti-CD25 antibody-immobilized material as a Treg-capturing device.

Large three-dimensional cell constructs for tissue engineering.

Much research has been conducted on fabricating biomimetic biomaterials in vitro. Tissue engineering approaches are often conducted by combining cells, scaffolds, and growth factors. However, the degradation rate of scaffolds is difficult to control and the degradation byproducts occasionally limit tissue regeneration. To overcome these issues, we have developed a novel system using a thermo-responsive hydrogel that forms scaffold-free, three-dimensional (3D) cell constructs with arbitrary size and morphology. 3D cell constructs prepared using bone marrow-derived stromal stem cells (BMSCs) exhibited self-organizing ability and formed bone-like tissue with endochondral ossification. Endothelial cells were then introduced into the BMSC construct and a vessel-like structure was formed within the constructs. Additionally, the bone formation ability was promoted by endothelial cells and cell constructs could be freeze-dried to improve their clinical application. A pre-treatment with specific protein protectant allowed for the fabrication of novel bone substitutes composed only of cells. This 3D cell construct technology using thermo-responsive hydrogels was then applied to other cell species. Cell constructs composed of dental pulp stem cells were fabricated, and the resulting construct regenerated pulp-like tissue within a human pulpless tooth. In this review, we demonstrate the approaches for the in vitro fabrication of bone and dental pulp-like tissue using thermo-responsive hydrogels and their potential applications.

Block catiomer with flexible cationic segment enhances complexation with siRNA and the delivery performance in vitro.

RNA interference (RNAi) by small interfering RNAs (siRNAs) is a promising therapeutic approach. Because siRNA has limited intracellular access and is rapidly cleared in vivo, the success of RNAi depends on efficient delivery technologies. Particularly, polyion complexation between block catiomers and siRNA is a versatile approach for constructing effective carriers, such as unit polyion complexes (uPIC), core-shell polyion complex (PIC) micelles and vesicular siRNAsomes, by engineering the structure of block catiomers. In this regard, the flexibility of block catiomers could be an important parameter in the formation of PIC nanostructures with siRNA, though its effect remains unknown. Here, we studied the influence of block catiomer flexibility on the assembly of PIC structures with siRNA using a complementary polymeric system, i.e. poly(ethylene glycol)-poly(L-lysine) (PEG-PLL) and PEG-poly(glycidylbutylamine) (PEG-PGBA), which has a relatively more flexible polycation segment than PEG-PLL. Mixing PEG-PGBA with siRNA at molar ratios of primary amines in polymer to phosphates in the siRNA (N/P ratios) higher than 1.5 promoted the multimolecular association of uPICs, whereas PEG-PLL formed uPIC at all N/P ratios higher than 1. Moreover, uPICs from PEG-PGBA were more stable against counter polyanion exchange than uPICs from PEG-PLL, probably due to a favorable complexation process, as suggested by computational studies of siRNA/block catiomer binding. In in vitro experiments, PEG-PGBA uPICs promoted effective intracellular delivery of siRNA and efficient gene knockdown. Our results indicate the significance of polycation flexibility on assembling PIC structures with siRNA, and its potential for developing innovative delivery systems.

Carbonate apatite artificial bone.

Bone apatite is not hydroxyapatite (HAp), it is carbonate apatite (CO3Ap), which contains 6-9 mass% carbonate in an apatitic structure. The CO3Ap block cannot be fabricated by sintering because of its thermal decomposition at the sintering temperature. Chemically pure (100%) CO3Ap artificial bone was recently fabricated through a dissolution-precipitation reaction in an aqueous solution using a precursor, such as a calcium carbonate block. In this paper, methods of fabricating CO3Ap artificial bone are reviewed along with their clinical and animal results. CO3Ap artificial bone is resorbed by osteoclasts and upregulates the differentiation of osteoblasts. As a result, CO3Ap demonstrates much higher osteoconductivity than HAp and is replaced by new bone via bone remodeling. Granular-type CO3Ap artificial bone was approved for clinical use in Japan in 2017. Honeycomb-type CO3Ap artificial bone is fabricated using an extruder and a CaCO3 honeycomb block as a precursor. Honeycomb CO3Ap artificial bone allows vertical bone augmentation. A CO3Ap-coated titanium plate has also been fabricated using a CaCO3-coated titanium plate as a precursor. The adhesive strength is as high as 76.8 MPa, with excellent tissue response and high osteoconductivity.

Current approaches for the exploration of antimicrobial activities of nanoparticles.

Infectious diseases of bacterial and viral origins contribute to substantial mortality worldwide. Collaborative efforts have been underway between academia and the industry to develop technologies for a more effective treatment for such diseases. Due to their utility in various industrial applications, nanoparticles (NPs) offer promising potential as antimicrobial agents against bacterial and viral infections. NPs have been established to possess potent antimicrobial activities against various types of pathogens due to their unique characteristics and cell-damaging ability through several mechanisms. The recently accepted antimicrobial mechanisms possessed by NPs include metal ion release, oxidative stress induction, and non-oxidative mechanisms. Another merit of NPs lies in the low likelihood of the development of microbial tolerance towards NPs, given the multiple simultaneous mechanisms of action against the pathogens targeting numerous gene mutations in these pathogens. Moreover, NPs provide a fascinating opportunity to curb microbial growth before infections: this outstanding feature has led to their utilization as active antimicrobial agents in different industrial applications, e.g. the coating of medical devices, incorporation in food packaging, promoting wound healing and encapsulation with other potential materials for wastewater treatment. This review discusses the progress and achievements in the antimicrobial applications of NPs, factors contributing to their actions, mechanisms underlying their efficiency, and risks of their applications, including the antimicrobial action of metal nanoclusters (NCs). The review concludes with a discussion of the restrictions on present studies and future prospects of nanotechnology-based NPs development.

Improved anti-cancer effect of epidermal growth factor-gold nanoparticle conjugates by protein orientation through site-specific mutagenesis.

Epidermal growth factor (EGF)-nanoparticle conjugates have the potential for cancer therapeutics due to the unique cytotoxic activity in cancer cells with EGF receptor (EGFR) overexpression. To gain its maximum activity, the EGF molecule should be immobilized on the nanoparticle surface in a defined orientation so as the bulky nanoparticle will not interfere EGF-EGFR interaction. Herein, we demonstrate successful enhancement of the anti-cancer activity of EGF-gold nanoparticle conjugates (EGF-GNPs) by controlling the EGF orientation on the surface of the nanoparticle through site-specific mutagenesis. Three lysine-free EGF variants (RR, RS, and SR) were designed, where two endogenous lysine residues were replaced with either arginine (R) or serine (S). The EGF mutants can be conjugated to the GNPs in a controlled orientation through the single amino group at the N-terminus. The ability of the mutants to induce extracellular signal-regulated kinase (ERK) phosphorylation was no different from wild type EGF (WT) in soluble form, rather lowered for one mutant (RR). However, after conjugated to GNPs, the SR mutants exhibited an enhanced biological activity than WT, in terms of ERK phosphorylation and growth inhibition of cancer cells. Further analysis of the binding constant of each mutant indicated the emergent enhanced activity of the GNP conjugates of the SR mutant was not solely contributed to the orientation, but to its higher binding activity to EGFR. These results validate the present genetic recombination strategy to improve the anticancer efficiency of EGF-GNPs.

Weakly acidic carboxy group-grafted ß-cyclodextrin-threaded acid-degradable polyrotaxanes for modulating protein interaction and cellular internalization.

To improve the therapeutic potential of ß-cyclodextrin (ß-CD)-threaded acid-degradable polyrotaxanes (ß-CD PRXs) in cholesterol-related metabolic disorders, we investigated the effect of carboxylation of ß-CD PRXs on intracellular uptake. In this study, we established a synthetic method for the modification of carboxylalkyl carbamates on ß-CD PRXs without degradation and synthesized three series of carboxyalkyl carbamate group-modified ß-CD PRXs with different alkyl spacer lengths. The modification of carboxymethyl carbamate (CMC), carboxyethyl carbamate (CEC), and carboxypropyl carbamate (CPC) on the ß-CD PRXs slightly reduced the interaction of the PRXs with the lipid layer model compared with the modification of 2-(2-hydroxyethoxy)ethyl carbamate (HEE-PRX), which was used in our previous studies. However, all the carboxylated ß-CD PRXs showed a significantly stronger interaction with a protein model compared with HEE-PRX. The carboxylated ß-CD PRXs showed significantly high intracellular uptake, through macrophage scavenger receptor A (MSR-A)-mediated endocytosis, in MSR-A-positive RAW 264.7 cells compared with HEE-PRX. Interestingly, the carboxylated ß-CD PRXs also showed significantly higher intracellular uptake even in MSR-A-negative cells compared with HEE-PRX. Carboxylated ß-CD PRXs are considered to strongly interact with other membrane proteins, resulting in high intracellular uptake. The length of the alkyl spacer affected the intracellular uptake levels of carboxylated PRXs, however, this relationship was varied for different cell types. Furthermore, none of the carboxylated ß-CD PRXs exhibited cytotoxicity in the RAW 264.7 and NIH/3T3 cells. Altogether, carboxylation of ß-CD PRXs is a promising chemical modification approach for their therapeutic application because carboxylated ß-CD PRXs exhibit high cellular internalization efficiency in MSR-A-negative cells and negligible toxicity.

Nanomaterials and their composite scaffolds for photothermal therapy and tissue engineering applications.

Photothermal therapy (PTT) has attracted broad attention as a promising method for cancer therapy with less severe side effects than conventional radiation therapy, chemotherapy and surgical resection. PTT relies on the photoconversion capacity of photothermal agents (PTAs), and a wide variety of nanomaterials have been employed as PTAs for cancer therapy due to their excellent photothermal properties. The PTAs are systematically or locally administered and become enriched in cancer cells to increase ablation efficiency. In recent years, PTAs and three-dimensional scaffolds have been hybridized to realize the local delivery of PTAs for the repeated ablation of cancer cells. Meanwhile, the composite scaffolds can stimulate the reconstruction and regeneration of the functional tissues and organs after ablation of cancer cells. A variety of composite scaffolds of photothermal nanomaterials have been prepared to combine the advantages of different modalities to maximize their therapeutic efficacy with minimal side effects. The synergistic effects make the composite scaffolds attractive for biomedical applications. This review summarizes these latest advances and discusses the future prospects.