No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Copper-Eluting Fibers for Enhanced Tissue Sealing and Repair
Abstract
Copper ions play an important role in several physiological processes, including angiogenesis, growth factor induction and extracellular matrix remodeling, that modulate wound healing and tissue repair. In this work, copper-loaded alginate fibers were generated and used as surgical sutures for repair of incisional wounds in live mice. Approximately 95% of initially loaded copper ions were released from the sutures within the first 24 hours following an initial burst release. This localized delivery of copper at the incision site resulted in significantly higher recovery in tissue biomechanical strengths compared to conventional nylon and calcium-alginate sutures at early times following surgery. Irradiation of copper-alginate sutures with near infrared light resulted in a robust photothermal response and led to efficacies similar to those seen with non-irradiated sutures. Histopathology and immunohistological analyses indicated significantly reduced epithelial gap and higher number of CD31+ cells, which is indicative of increased angiogenesis around the incision site. Delivery of copper ions did not result in toxicity under the conditions employed. Our findings demonstrate that delivery of ionic copper from sutures resulted in efficacious approximation and healing of incisional wounds, and copper-eluting fibers may have translational potential for accelerating repair in surgical and trauma wounds.
... Upon interaction with Cu ions, bacterial cell membranes change permeability, leading to the inactivation of enzymes. Consequently, the leakage of DNA, RNA, proteins, and cytoplasm ensues, resulting in bacterial death [63,64]. In this study, the antibacterial effect of copper was demonstrated, aligning with the findings in existing literature. ...
... Copper is also involved in the modulation of integrins by differentiated keratinocytes during the remodelling phase. 34 The capacity of copper to enhance faster closure of full-thickness wounds has been demonstrated in several wound animal models, [35][36][37] including in diabetic mice. 38 In accordance, copper chelation delays wound closure. ...
Objective:
The quest for an ideal wound dressing has been a longstanding challenge due to the complex nature of wound healing, including stages of haemostasis, inflammation, maturation and remodelling, with overlapping timelines. This makes it difficult to find a single dressing that optimally supports all phases of wound healing. In addition, the ideal wound dressing should possess antibacterial properties and be capable of effectively debriding and lysing necrotic tissue. Copper is an essential trace element that participates in many of the key physiological wound healing processes.
Method:
Copper stimulates secretion of various cytokines and growth factors, thus promoting angiogenesis, granulation tissue formation, extracellular matrix proteins secretion and re-epithelialisation. Harnessing this knowledge, we have used copper oxide-impregnated wound dressings in numerous cases and observed their benefits throughout the entire wound healing process.
Results:
This led us to postulate the 'continuum of care' hypothesis of copper dressings. In this study we describe four cases of hard-to-heal wounds of various aetiologies, in which we applied copper dressings consistently across all stages of wound healing, with rapid uneventful healing.
Conclusion:
We believe we have successfully implemented the continuum of care principle.
... It is a p-type semiconductor with a narrow band gap of 1.2 eV and has been reported as a promising material for different applications due to its chemical stability, nontoxic nature, high efficiency, and low production cost [32,33]. In addition, the antibacterial activity of copper ions (Cu 2+ ) has been reported by many researchers [34,35] and Cu 2+ has been reported to possess other valuable biological features such as enhancing the cell activity and proliferation of osteoblastic cells [36], improving the angiogenesis of bioactive scaffolds, wound healing [37], anti-cancer [38,39], and biological imaging probes [40]. Owing to these distinct properties, it is noteworthy to investigate the antimicrobial activities of CuO [41]. ...
With the aid of a facile and green aqueous solution approach, a variety of copper oxide (CuO) with different shapes and polyacrylic-acid (PAA)-regulated silver-carried CuO (CuO@Ag) nanosheet composites have been successfully produced. The point of this article was to propose a common synergy using Ag-carried CuO nanosheet composites for their potential antibacterial efficiency against three types of bacteria such as E. coli, P. aeruginosa, and S. aureus. By using various technical means such as XRD, SEM, and TEM, the morphology and composition of CuO and CuO@Ag were characterized. It was shown that both CuO and CuO@Ag have a laminar structure and exhibit good crystallization, and that the copper source and reaction duration have a sizable impact on the morphology and size distribution of the product. In the process of synthesizing CuO@Ag, the appropriate amount of polyacrylic acid (PAA) can inhibit the agglomeration of Ag NPs and regulate the size of Ag at about ten nanometers. In addition, broth dilution, optical density (OD 600), and electron microscopy analysis were used to assess the antimicrobial activity of CuO@Ag against the above three types of bacteria. CuO@Ag exhibits excellent synergistic and antibacterial action, particularly against S. aureus. The antimicrobial mechanism of the CuO@Ag nanosheet composites can be attributed to the destruction of the bacterial cell membrane and the consequent leakage of the cytoplasm by the release of Ag+ and Cu2+. The breakdown of the bacterial cell membrane and subsequent leakage of cytoplasm caused by Ag+ and Cu2+ released from antimicrobial agents may be the cause of the CuO@Ag nanosheet composites’ antibacterial action. This study shows that CuO@Ag nanosheet composites have good antibacterial properties, which also provides the basis and ideas for the application research of other silver nanocomposites.
... Given this, to solidify the NADESs, eutectogels enabled by gelling the NADESs (Zeng et al., 2020) are expected to be fabricated using safe, biodegradable and nontoxic backbone materials. As water-insoluble calcium alginate (CA) hydrogels have good biocompatibility, high safety and suitable mechanical properties (Ghosh et al., 2020;Xin et al., 2020), which are widely used in the food and biomedical fields to load functional substances (Gholamian et al., 2021;Song et al., 2020;Wu et al., 2020), NADESs-incorporated CA (NADESs@CA) eutectogels are proposed to be fabricated, hoping to explore a greener way of bio-inspired anti-freezing materials in the frozen food industry. ...
To explore food-grade anti-freezing strategies for the frozen food industry, three bio-inspired binary natural deep eutectic solvents (NADESs) comprising proline, glucose, and sorbitol were prepared. Besides, through gelling the NADESs, two-dimensional planar film-like eutectogels (PG53, PG11, and PS11) showing sandwich-like structures were fabricated, of which basic characteristics, anti-frosting capacities and freezing-tolerance were investigated. Results indicated that the eutectogels possessing plenty of hydroxy groups within systems could show more hydrophilic surfaces (47.6°–55.7°) as compared with the control group (69.1°). Besides, PS11 showed the best anti-frosting capacity, exhibiting only 36.31% frost-covered area after 120 min under extreme conditions, probably due to its more rugged surface possessing more and spikier hill-like profiles. For freezing-tolerance, all the eutectogels could stay flexible at −40 °C and show stable mechanical strengths before (stress: 3.1–4.4 MPa, strain: 82.6%–104.7%) and after (stress: 2.5–3.9 MPa, strain: 71.9%–96.5%) extreme temperature fluctuation. Given this, an absorption-inhibition hypothesis was proposed and verified by gradient moisture absorption test and cooling-heating cyclic test, through which critical absorption relative humidity (CARH) and glass transition temperature (Tg) were obtained, which suggested that the eutectogels firstly absorbed the ambient moisture easily (CARH: 49% RH ∼ 55% RH) and subsequently inhibited the crystallization through immobilizing the moisture within the NADESs systems (Tg: -58.6 °C ∼ -50.5 °C), endowing them with great potentials for interfacial anti-frosting. It is hoped that this work could broaden the field of bio-inspired anti-freezing materials in a greener and eco-friendly way.
... The capacity of copper to enhance faster closure of full-thickness wounds was demonstrated in several wound animal models, [30,39,40], including in diabetic mice [41]. ...
Copper has two key properties that endow it as an excellent active ingredient to be used in the “wound healing battle”. First, copper plays a key role in angiogenesis, dermal fibroblasts proliferation, upregulation of collagen and elastin fibers production by dermal fibroblasts, and it serves as a cofactor of Lysyl oxidase needed for efficient dermal extracellular matrix (ECM) protein cross-linking. Secondly, copper has potent wide-spectrum biocidal properties. Both gram-positive and gram-negative bacteria, including antibiotic resistant bacteria and hard to kill bacterial spores, fungi and viruses, when exposed to high copper concentrations, are killed. Copper has been used as a biocide for centuries by many different civilizations. Impregnation of copper oxide microparticles in wound dressings allows continuous release of copper ions. This results not only in the protection of the wounds and wound dressings from pathogens, but more importantly, enhances wound healing. The article discusses the molecular mechanisms of enhanced wound healing by the copper oxide impregnated dressings, which include in situ upregulation of pro-angiogenic factors and increased blood vessel formation. It also includes clinical cases showing clearance of infection, induction of granulation and epithelialization of necrotic wounds, reduction of post-operative swelling inflammation and reduction of scar formation, in wounds when they were treated with copper oxide impregnated dressings. We show the positive outcome at all wound healing stages of using the copper impregnated wound dressings, indicating the neglected critical role copper plays in wound healing.
... In addition to the above-mentioned functions of copper-containing biomaterials, Ghosh Deepanjan et al. found that delivery of ionic copper from sutures could promote incisional wounds healing, and coppereluting fibers may have translational potential for accelerating repair on surgical and trauma wounds [134]. L. A. Volodina et al. developed ointment containing copper nano-particles (NPs), which could provide a high level of reparation of skin wounds [135]. ...
Copper is an indispensable trace metal element in the human body, which is mainly absorbed in the stomach and small intestine and excreted into the bile. Copper is an important component and catalytic agent of many enzymes and proteins in the body, so it can influence human health through multiple mechanisms. Based on the biological functions and benefits of copper, an increasing number of researchers in the field of biomaterials have focused on developing novel copper-containing biomaterials, which exhibit unique properties in protecting the cardiovascular system, promoting bone fracture healing, and exerting antibacterial effects. Copper can also be used in promoting incisional wounds healing, killing cancer cells, Positron Emission Tomography (PET) imaging, radioimmunological tracing and radiotherapy of cancer. In the present review, the biological functions of copper in the human body are presented, along with an overview of recent progress in our understanding of the biological applications and development of copper-containing materials. Furthermore, this review also provides the prospective on the challenges of those novel biomaterials for future clinical applications.
The employment of metal-organic framework (MOF)-based nanomaterials has been rapidly increasing in bioapplications owing to their biocompatibility, drug degradation, tunable porosity, and intrinsic biodegradability. This evidence suggests that the multifunctional bimetallic ions can behave as remarkable candidates for infection control and wound healing. In this study, bimetallic MOFs (Zn-HKUST-1 and FolA-Zn-HKUST-1) embedded with and without folic acid were synthesized and used for tissue sealing and repairing incisional wound sites in mice models. For comparison, HKUST-1 and FolA-HKUST-1 were also synthesized. The Brunauer-Emmett-Teller (BET) surface area measured for HKUST-1, FolA-HKUST-1, Zn-HKUST-1, and FolA-Zn-HKUST-1 from N2 isotherms was found to be 1868, 1392, 1706, and 1179 m2/g, respectively. The measurements of contact angle values for Zn-HKUST-1, FolA-HKUST-1, and Zn-FolA-HKUST-1 were identified as 4.95 ± 0.8, 43.6 ± 3.4, and 60.62 ± 2.0°, respectively. For topical application in wound healing, they display a wide range of healing characteristics, including antibacterial and enhanced wound healing rates. In addition, in vitro cell migration and tubulogenic potentials were evaluated. The significant reduction in the wound gap and increased expression levels for CD31, eNOS, VEGF-A, and Ki67 were observed from immunohistological analyses to predict the angiogenesis behavior at the incision wound site. The wound healing rate was analyzed in the excisional dermal wounds of diabetic mice model in vivo. On account of antibacterial potentials and tissue-repairing characteristics of Cu2+ and Zn2+ ions, designing an innovative mixed metal ion-based biomaterial has wide applicability and is expected to modulate the growth of various gradient tissues.
As one of the long-established and necessary medical devices, surgical sutures play an essentially important role in the closing and healing of damaged tissues and organs postoperatively. The recent advances in multiple disciplines, like materials science, engineering technology, and biomedicine, have facilitated the generation of various innovative surgical sutures with humanization and multi-functionalization. For instance, the application of numerous absorbable materials is assuredly a marvelous progression in terms of surgical sutures. Moreover, some fantastic results from recent laboratory research cannot be ignored either, ranging from the fiber generation to the suture structure, as well as the suture modification, functionalization, and even intellectualization. In this review, the suture materials, including natural or synthetic polymers, absorbable or non-absorbable polymers, and metal materials, were first introduced, and then their advantages and disadvantages were summarized. Then we introduced and discussed various fiber fabrication strategies for the production of surgical sutures. Noticeably, advanced nanofiber generation strategies were highlighted. This review further summarized a wide and diverse variety of suture structures and further discussed their different features. After that, we covered the advanced design and development of surgical sutures with multiple functionalizations, which mainly included surface coating technologies and direct drug-loading technologies. Meanwhile, the review highlighted some smart and intelligent sutures that can monitor the wound status in a real-time manner and provide on-demand therapies accordingly. Furthermore, some representative commercial sutures were also introduced and summarized. At the end of this review, we discussed the challenges and future prospects in the field of surgical sutures in depth. This review aims to provide a meaningful reference and guidance for the future design and fabrication of innovative surgical sutures. STATEMENT OF SIGNIFICANCE: This review article introduces the recent advances of surgical sutures, including material selection, fiber morphology, suture structure and construction, as well as suture modification, functionalization, and even intellectualization. Importantly, some innovative strategies for the construction of multifunctional sutures with predetermined biological properties are highlighted. Moreover, some important commercial suture products are systematically summarized and compared. This review also discusses the challenges and future prospects of advanced sutures in a deep manner. In all, this review is expected to arouse great interest from a broad group of readers in the fields of multifunctional biomaterials and regenerative medicine.
The mechanical mismatch between soft hydrated tissues and sutures has become a common negative impact on wound healing process. A novel method of coating multilayer polymer shells is thus reported to improve the mechanical performance of hydrogel sutures. It is suitable for tissue patching and shows advantages of convenient, efficient, and biosafety. Specifically, a precursor hydrogel ([email protected]) consisted of carboxymethyl chitosan and copper modified by carbon dots was used as the inner sheath, and then bonding the precursor hydrogel sheath with toughening polyethylene glycol network by anchoring sites composited from rigid chitosan shell integrated a whole structure. Subsequently, the whole system was soaked with EtOH, and rapid dehydration of EtOH was used to accelerate the entanglement process between the two coatings by constricting the molecular chains. Finally, an ideal suture (Cu-fiber) with both toughness and rigidness was obtained. The data showed that the tensile strength and biosafety of the hydrogel sutures prepared by the new strategy were significantly improved, and the skin, liver and vessel of rodents can be sutured without secondary damage. Moreover, it can inhibit inflammation response and promote the healing process of skin wound, indicating that the Cu-fiber will become a great candidate for tissue patching.
Copper, an essential trace element for human life, can crosslink with biopolymers and participate in multitudinous physiological processes. In this study, the electrophoretic deposition (EPD) technique, as a novel and efficient approach, was applied for the facile and rapid fabrication of citrus peel pectin/copper composite hydrogels. The results demonstrated that a pectin concentration of 0.75% (w/w) and a voltage of 3 V were adequate for the electroformation of hydrogels. The weight of these hydrogels reached 412.9 ± 8.69 and 694.78 ± 11.23 mg at 60 min (CPP-60) and 120 min (CPP-120), respectively, while the thickness of CPP-60 and CPP-120 reached to 1.23 ± 0.11, 2.41 ± 0.20 mm, respectively. Furthermore, the weight and thickness of these hydrogels shared a solid linear relationship with time, providing excellent support for electrogelation in simple 3D printing. As such, three shaped hydrogels were printed successfully by EPD with a CPP concentration of 0.75% (w/w) and voltage of 3 V for 15 min. Especially, the Cu²⁺ ions release profiles of CPP-60 and CPP-120 were measured by inductively coupled plasma atomic emission spectroscopy (ICP-OES), which demonstrated good copper ions release performance and antibacterial activities.
Variant modalities are quested and merged into the tumor nanotherapy by leveraging the excitation from external or intratumoral incentives. However, the ubiquitous hypoxia and the insufficient content of hydrogen peroxide (H2O2) in tumor microenvironments inevitably hinder the effective production of reactive oxygen species (ROS). To radically extricate from the shackles, peroxymonosulfate (PMS: HSO5−)‐loaded hollow mesoporous copper sulfide (CuS) nanoparticles (NPs) are prepared as the distinct ROS donors for sulfate radical (•SO4−)‐mediated and stimuli‐responsive tumor nanotherapy in an oxygen‐independent manner. In this therapeutic modality, the second near‐infrared laser irradiation, together with the released copper ions as well as the heat produced by CuS after illumination, work together to activate PMS thus triply ensuring the copious production of •SO4−. Different from conventional ROS, the emergence of •SO4−, possessing a longer half‐life and more rapid reaction, is independent of the oxygen (O2) and H2O2 content within the tumor. In addition, this engineered nanosystem also exerts the function of photoacoustic imaging and skin restoration on the corresponding animal models. This study reveals the enormous potential of sulfate radical in oncotherapy and broadens pave for exploring the application of multifunctional and stimuli‐responsive nanosystems in biomedicine. The CuS@PMS nanosystems with multiple theranostic functions are maneuverable in stimuli‐responsive sulfate radical‐mediated nanotherapy against melanoma in an oxygen‐independent manner, competent in photoacoustic imaging and precipitating skin regeneration. The high‐performance sulfate radical tumor therapy is implemented via exploiting the outstanding oxidation property of sulfate radical and inducing synergistic activation by photothermal effect and copper ions.
Self‐regenerative hydrogels have recently been developed, and represent a special type of self‐healing hydrogels with the ability to restore a dehydrated hydrogel with physical damage. In this study, a self‐regenerative hydrogel (COCu) based on two chitosan polymers assembled by slow‐released Cu²⁺ is developed. The COCu hydrogel displays an excellent regeneration ability after being dehydrated and fractured. By simple hydration at room temperature, the fragments of the dehydrated gel fuse into one seamless whole, thereby preserving the mechanical properties and functionalities of the original hydrogel. The regeneration process can be conducted repeatedly after different methods of dehydration (natural volatilization, heat drying, lyophilization) and various modes of deconstruction (flakes, powder, lumpy sponge, etc.). Furthermore, the COCu hydrogel provides ultra‐stretchability, and it can be stretched into thin (0.01–0.1 mm) filaments, which, when dried (dtCOCu), can be used as suture lines. Moreover, when used as a dry suture, it regenerates into the hydrogel in the presence of the tissue fluid, forming an excellent sealant to immobilize tissues and seamlessly seal wounds. The fast self‐regeneration allows for its facile application as both a hydrated gel dressing and dry suture, and offers customized strategies for fixing and repair of different wounds in soft tissues.
How to accelerate tendon healing remains a clinical challenge. In this study, a suture carrying nanoparticle/pEGFP-basic fibroblast growth factor (bFGF) and pEGFP-vascular endothelial growth factor A (VEGFA) complexes was developed to transfer the growth factor genes into injured tendon tissues to promote healing. Polydopamine-modified sutures can uniformly and tightly absorb nanoparticle/plasmid complexes. After tendon tissues were sutured, the nanoparticle/plasmid complexes still existed on the suture surface. Further, we found that the nanoparticle/plasmid complexes delivered into tendon tissues could diffuse from sutures to tendon tissues and effectively transfect genes into tendon cells, significantly increasing the expression of growth factors in tendon tissues. Finally, biomechanical tests showed that nanoparticle/pEGFP-bFGF and pEGFP-VEGFA complex-coated sutures could significantly increase the ultimate strengths of repaired tendons, especially at 4 weeks after operation. Two kinds of nanoparticle/plasmid complex-coated sutures significantly increased flexor tendon healing strength by 3.7 times for Ethilon and 5.8 times for PDS II, respectively, compared with the corresponding unmodified sutures. In the flexor tendon injury model, at 6 weeks after surgery, compared with the control suture, the nanoparticle/plasmid complex-coated sutures can significantly increase the gliding excursions of the tendon and inhibit the formation of adhesion. These results indicate that this nanoparticle/plasmid complex-coated suture is a promising tool for the treatment of injured tendons.
The surgical suture has long been used to reconnect the injured tissues to restore their structure and function. However, its utility remains challenging in many areas, such as surgical site infections and minimally invasive surgeries. Herein, we report a novel surgical suture that possesses both antibacterial activity and shape memory effect to address these issues. In detail, natural antibacterial berberine was incorporated directly into the spinning solution of shape memory polyurethane with a near body transition temperature, and then berberine-containing polyurethane (BP) fibers were prepared by a facile one-step wet-spinning method for surgical suture. The prepared BP fibers were micro-sized and characterized by their transition temperature, morphology, water contact angles, mechanical properties, in vitro shape memory effect, drug release, and antibacterial activity. The results showed that with the increasing amount of the incorporated berberine, the transition temperatures of the fibers were not significantly affected, remains at near body temperature, while the contact angles of the fibers were significantly decreased and the mechanical properties of the fibers were significantly weakened. The optimized fiber was selected to evaluate the cytotoxicity and in vivo biocompatibility before in vivo shape memory effect and wound healing capacity in a mouse skin suture–wound model was tested. Besides the shape memory effect, it was demonstrated that the fiber is capable of antibacterial activity and anti-inflammatory effect, and promoting wound healing. The mechanism of the antibacterial activity and anti-inflammatory effect of the fiber was discussed. Overall, it is expected that by the berberine added to the fiber for surgical suture, it will be more popular and extend the utility of the sutures in a wide range of clinical applications.
Calcium alginate (CA) beads as a green sorbent were easily fabricated in this study using sodium alginate crosslinking with CaCl2, and the crosslinking pathway was the exchange between the sodium ion of α-L-guluronic acid and Ca(II). The experimental study was conducted on Cu(II), Cd(II), Ni(II) and Zn(II) as the model heavy metals and the concentration was determined by inductively coupled plasma optical emission spectrometry (ICP-OES). The characterization and sorption behavior of the CA beads were analyzed in detail via using scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The adsorption experiments demonstrated that the CA beads exhibited a high removal efficiency for the selective adsorption of Cu(II) from the tetra metallic mixture solution and an excellent adsorption capacity of the heavy metals separately. According to the isotherm studies, the maximum uptake of Cu(II) could reach 107.53 mg/g, which was significantly higher than the other three heavy metal ions in the tetra metallic mixture solution. Additionally, after five cycles of adsorption and desorption, the uptake rate of Cu(II) on CA beads was maintained at 92%. According to the properties mentioned above, this material was assumed to be applied to reduce heavy metal pollution or recover valuable metals from waste water.
Study Design
Systematic review.
Objectives
In patients undergoing posterior spinal fusion: (1) What are the types and risks of wound complications in major (≥3 levels) surgery, and does the risk vary by number of levels fused? (2) What types of fascial closure result in the fewest wound complications? (3) What subcutaneous closure technique is more effective in preventing wound complications for obese patients (body mass index >30 kg/m²)? (4) What type of skin closure results in the fewest wound complications? (5) What type of dressing results in the fewest wound complications?
Methods
Electronic databases and reference lists of key articles were searched from January 1, 2000 to December 4, 2017 to identify studies meeting inclusion criteria.
Results
Six lower quality retrospective studies (evidence level III) met the inclusion criteria. The risk of wound complications in patients with ≥3 level posterior spine fusion ranges from 1.5% to 3.7% depending on the definition of wound complications. Skin closure with sutures resulted in fewer wound infections compared with staples (0.0% vs 8.0%, P = .023). We were unable to demonstrate an association between the number of levels fused and infection risk. Wound infections, primarily superficial, occurred less frequently with Silverlon dressing versus routine dressing.
Conclusions
We were unable to determine if infection risk changed with increasing number of levels fused. There is a lack of evidence for optimal wound closure technique in posterior spine surgery. Several questions still remain unanswered, such as the optimal fascial closure technique or the optimal subcutaneous closure technique in obese patients.
Surgical excision of skin cancers can hardly remove the tumor tissues completely and simultaneously result in cutaneous defects. To avoid tumor recurrence and heal the tumor-induced wounds, we designed a tissue engineering membranes possessing bifunctions of tumor therapy and skin tissue regeneration. The micropatterned nanocomposite membrane was successfully fabricated by incorporating Cu2S nanoflowers into biopolymer fibers via a modified electrospinning method. With uniformly-embedded Cu2S nanoparticles, the membranes exhibited excellent and controllable photothermal performance under near-infrared (NIR) irradiation, which resulted in high mortality (> 90 %) of skin tumor cells and effectively inhibited tumor growth in mice. Moreover, the membranes supported the adhesion, proliferation and migration of skin cells as well as significantly stimulated angiogenesis and healed full-thickness skin defects in vivo. This proof-of-concept study offers a facile and reliable strategy for localized skin tumor therapy and tissue regeneration using bifunctional tissue engineering biomaterials, showing great promises for tumor-induced wound healing application.
Purpose
To develop and evaluate an antibiotic-eluting suture for ophthalmic surgery.
Methods
Wet electrospinning was used to manufacture sutures composed of poly(L-lactide), polyethylene glycol (PEG), and levofloxacin. Size, morphology, and mechanical strength were evaluated via scanning electron microscopy and tensile strength, respectively. In vitro drug release was quantified using high performance liquid chromatography. In vitro suture activity against Staphylococcus epidermidis was investigated through bacterial inhibition studies. Biocompatibility was determined via histological analysis of tissue sections surrounding sutures implanted into Sprague-Dawley rat corneas.
Results
Sutures manufactured via wet electrospinning were 45.1 ± 7.7 μm in diameter and 0.099 ± 0.007 newtons (N) in breaking strength. The antibiotic release profile demonstrated a burst followed by sustained release for greater than 60 days. Increasing PEG in the polymer formulation, from 1% to 4% by weight, improved drug release without negatively affecting tensile strength. Sutures maintained a bacterial zone of inhibition for at least 1 week in vitro and elicited an in vivo tissue reaction comparable to a nylon suture.
Conclusions
There is a need for local, postoperative delivery of antibiotics following ophthalmic procedures. Wet electrospinning provides a suitable platform for the development of sutures that meet size requirements for ophthalmic surgery and are capable of sustained drug release; however, tensile strength must be improved prior to clinical use.
Translational Relevance
No antibiotic-eluting suture exists for ophthalmic surgery. A biocompatible, high strength suture capable of sustained antibiotic release could prevent ocular infection and preclude compliance issues with topical eye drops.
Over the last decades, alginates, natural multifunctional polymers, have increasingly drawn attention as attractive compounds in the biomedical and pharmaceutical fields due to their unique physicochemical properties and versatile biological activities. The focus of the paper is to describe biological and pharmacological activity of alginates and to discuss the present use and future possibilities of alginates as a tool in drug formulation. The recent technological advancements with using alginates, issues related to alginates suitability as matrix for three-dimensional tissue cultures, adjuvants of antibiotics, and antiviral agents in cell transplantation in diabetes or neurodegenerative diseases treatment, and an update on the antimicrobial and antiviral therapy of the alginate based drugs are also highlighted.
Chronic nonhealing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications, possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein the authors set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST-1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) are synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel is determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes are measured. Wound closure rates and wound blood perfusion are assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NPs disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) are protected from degradation and copper ions are slowly released. Cytotoxicity and apoptosis due to copper ion release are significantly reduced while dermal cell migration in vitro and wound closure rates in vivo are significantly enhanced. In vivo, H-HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.
Statement of significance:
A mechanically robust pure collagen suture was fabricated via linear electrocompaction and conjugated with heparin for prolonged delivery of PDFG-BB. Sustained delivery of the PDGF-BB improved the proliferation of tendon derived cells substantially at the expense of a moderate downregulation of tenogenic markers. The collagen threads were functionally applicable as epitendinous sutures when applied to chicken flexor tendons in vitro. Overall, electrocompacted collagen sutures holds potential to improve repair outcome in flexor tendon surgeries by improving cellularity and collagen production through delivery of the PDGF-BB. The bioinductive suture concept can be applied to deliver other growth factors for a wide-array of applications.
Electron transition materials on the basis of transition metal ions usually possess higher photothermal transduction efficiency but lower extinction ability, which haven't been considered as efficient photothermal agents for therapeutic applications. In this work, we demonstrate a facile and feasible approach for enhancing 808 nm photothermal conversion effect of d orbits transition Cu(II) ions by forming Cu-carboxylate complexes. The coordination with carboxylate groups greatly enlarges the splitting energy gap of Cu(II) and the capability of electron transition, thus enhancing the extinction ability in near-infrared (NIR) region. The cupreous complexes are further loaded in biocompatible and biodegradable polymer nanoparticles (NPs) of chitosan to temporarily lower the toxicity, which allows the photothermal therapy of human oral epithelial carcinoma (KB) cells in vitro and KB tumors in vivo. Animal experiments indicate the photothermal tumor inhibition rate of 100%. In addition, the gradual degradation of chitosan NPs leads to the release of cupreous complexes, thus exhibiting additional chemotherapeutic behavior in KB tumor treatment. Onefold chemotherapy experiments indicate the tumor inhibition rate of 93.1%. The combination of photothermal therapy and chemotherapy of cupreous complex-loaded chitosan NPs indicates the possibility in inhibiting tumor recurrence.
The present work describes synthesis of copper alginate-cotton cellulose (CACC) composite fibers and detailed investigation of antimicrobial action against the model bacteria E.coli. The CACC fibers were prepared by immersing cotton fibers in aqueous solution of sodium alginate, followed by ionic crosslinking of alginate chains within the cotton cellulose fibers with Cu(II) ions to yield CACC composite fibers. The resulting CACC fibers were investigated for their biocidal action against E.coli, by using zone inhibition and colonies counting method. Finally, CACC fibers were reduced with sodium borohydride to yield copper nanoparticles- loaded composite fibers and investigated for biocidal action. It was found that CACC fibers possessed both, the fair mechanical strength and antibacterial action. The extent of biocidal action was found to depend upon the amount of Cu(II) loaded and concentration of alginate into cotton- cellulose fibers. The fibers showed higher Cu(II) release in physiological fluid as compared to distilled water. Copper alginate-cotton cellulose (CACC) fibers show fair mechanical strength and release copper ions in the presence of physiological fluid and protein solution. These fibers have great potential to be used as dressing materials.
The fibrinolytic activity of plasmin plays a fundamental role in resolution of blood clots and clearance of extravascular deposited fibrin in damaged tissues. These vital functions of plasmin are exploited by malignant cells to accelerate tumor growth and facilitate metastases. Mice lacking functional plasmin thus display decreased tumor growth in a variety of cancer models. Interestingly, this role of plasmin has, in regard to skin cancer, been shown to be restricted to male mice. It remains to be clarified whether gender also affects other phenotypic characteristics of plasmin deficiency or if this gender effect is restricted to skin cancer. To investigate this, we tested the effect of gender on plasmin dependent immune cell migration, accumulation of hepatic fibrin depositions, skin composition, and skin wound healing. Gender did not affect immune cell migration or hepatic fibrin accumulation in neither wildtype nor plasmin deficient mice, and the existing differences in skin composition between males and females were unaffected by plasmin deficiency. In contrast, gender had a marked effect on the ability of plasmin deficient mice to heal skin wounds, which was seen as an accelerated wound closure in female versus male plasmin deficient mice. Further studies showed that this gender effect could not be reversed by ovariectomy, suggesting that female sex-hormones did not mediate the accelerated skin wound healing in plasmin deficient female mice. Histological examination of healed wounds revealed larger amounts of fibrotic scars in the provisional matrix of plasmin deficient male mice compared to female mice. These fibrotic scars correlated to an obstruction of cell infiltration of the granulation tissue, which is a prerequisite for wound healing. In conclusion, the presented data show that the gender dependent effect of plasmin deficiency is tissue specific and may be secondary to already established differences between genders, such as skin thickness and composition.
Local inflammatory reaction and tension are the main causes of postoperative complications after tracheal surgery. Adipose-derived stem cells (ASCs) are known to have immunomodulatory activity. The exact mechanism of this activity is not known, although it is possible that they modulate the function of different cells involved in the immune response. Little is known of their impact on acute inflammation, especially in the problematic tracheal area. We aimed to study the effect of ASCs applied locally in an animal model of tracheal resection and anastomosis.
ASCs from the subcutaneous fat of BDIX rats were infected for expression of the enhanced green fluorescent protein (eGFP) and were cultured with Polyglactin 910 sutures to obtain biosutures (ASC-coated sutures). After tracheal resection, 90 BDIX rats (syngeneic, autologous model) underwent anastomosis with biosutures (1.5 10(6) cells/biosuture [Group 1] or 0.5 10(6) cells/biosuture [Group 2]) or conventional sutures (Group 3). The animals were killed after 1, 4, 10, 30 or 60 days and histological and immunofluorescence studies were performed on the anastomotic areas. Inflammatory cell densities were graded semiquantitatively by the pathologist in a blinded fashion.
In the early period (1 and 4 days), the biosuture groups presented an atypical pattern of acute inflammation, characterized by the almost complete absence of neutrophils, and the presence of abundant lymphocytes and plasma cells, compared with the control group (P < 0.05). Moreover, abundant macrophages/monocytes were immunolocated around blood vessels near the biosutures and between biosuture threads 1 day after anastomosis, whereas the presence of macrophages/monocytes in animals treated with conventional sutures was discrete (P < 0.05). No differences were observed in the later period. No side effects in the biosuture groups were found.
Biosutures are a comfortable way of stem cell delivery to the surgical field without modification of the operative protocol. ASCs suppress the local acute inflammatory reaction (increased macrophage migration and decreased neutrophil infiltration) in the tracheal anastomosis and cause an early switch from acute to chronic inflammation.
Cell encapsulation, a strategy whereby a pool of live cells is entrapped within a semipermeable membrane, represents an evolving branch of biotechnology and regenerative medicine. For example, over the last 20 years, male and female gametes and embryos have been encapsulated with or without somatic cells for different purposes, such as in vitro gametogenesis, embryo culture, cell preservation and semen controlled release. Beside that, cell encapsulation technology in alginate, which is a natural biodegradable polymer that mimics the extracellular matrix and supports both cell functions and metabolism, has been developed with the aim of obtaining three-dimensional (3D) cultures. In this context, adipose-derived stromal vascular fraction (SVF) has attracted more and more attention because of its enormous potential in tissue regeneration. In fact, the SVF represents a rich source of mesenchymal cells (ADSCs), potentially able to differentiate into adipocytes, chondrocytes, osteoblasts, myocytes, cardiomyocytes, hepatocytes, and neuronal, epithelial and endothelial cells. These cells are ideal candidates for use in regenerative medicine, tissue engineering, including gene therapy and cell replacement cancer therapies. As long as technological resources are available for large-scale cell encapsulation intended for advanced therapies (gene therapy, somatic cell therapy and tissue engineering), the state-of-the-art in this field is reviewed in terms of scientific literature.
Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. Whereas a direct role of copper to facilitate angiogenesis has been evident two decades ago, the specific targets of copper action remained unclear. This report presents first evidence showing that inducible VEGF expression is sensitive to copper and that the angiogenic potential of copper may be harnessed to accelerate dermal wound contraction and closure. At physiologically relevant concentrations, copper sulfate induced VEGF expression in primary as well as transformed human keratinocytes. Copper shared some of the pathways utilized by hypoxia to regulate VEGF expression. Topical copper sulfate accelerated closure of excisional murine dermal wound allowed to heal by secondary intention. Copper-sensitive pathways regulate key mediators of wound healing such as angiogenesis and extracellular matrix remodeling. Copper-based therapeutics represents a feasible approach to promote dermal wound healing.
After resection and repair of the intestines, tissue degradation leads to weakening of the repair site and risk of postoperative leakage. Matrix metalloproteinases (MMPs) are thought to be responsible for collagenolysis in the direct vicinity of surgical sutures in many tissues. Several experimental studies show that MMP inhibitors administered systemically alleviate postoperative weakening of intestinal anastomoses. We hypothesised that local delivery of MMP inhibitors would achieve a similar effect.
Implementing a novel method for the coating of biomaterials, we coated sutures with a cross-linked fibrinogen film and bound the MMP inhibitor doxycycline into this film. The sutures were then used in a standard rat model for evaluating mechanical properties of colonic anastomoses 3 days after surgery.
The breaking strength of the anastomoses on the critical third day after operation was 17% higher with doxycycline-coated sutures compared to controls (P = 0.026). Energy uptake at failure was enhanced by 20% (P = 0.047).
Drug delivery by means of MMP-inhibitor-coated sutures appears to improve tissue integrity during anastomotic repair and may reduce postoperative complications.
Development of biocompatible and bioactive drug-loaded sutures is considered as an effective but challenging strategy for wound healing process by delivering biological drugs (e.g. antibiotics) or growth factors (e.g. bFGF) at the surgical wound sites. Conventional offline sutures strategies often lead to fast and uncontrollable release of drugs at wound sites, rendering wound healing become a longer and painful process for patients. Herein, we propose an online suture strategy to fabricate electrospun polycaprolactone (PCL) fibrous yarns, incorporated with both collagen (COL) and bFGF growth factor, to produce [email protected] sutures. Upon demonstrating the well-oriented and aligned fibrous microstructure, high mechanical properties, and controlled release of bFGF from [email protected] sutures in vitro, we then applied [email protected] sutures to an incision wound healing mouse model in vivo. Further in vivo study showed that as compared to the commercialized vicryl suture, [email protected] sutures significantly promoted the wound healing at different stages by accelerating granulation tissue formation, collagen deposition, and re-epithelialization. The enhanced wound healing efficiency of [email protected] sutures is likely attributed to two synergistic factors: (i) the well-oriented nanofibrous structure reduces tissue drag to minimize their trauma and (ii) the presence of both collagen and bFGF enhances the basement membrane (BM) reconstruction, cell proliferation, and angiogenesis. This work demonstrates effective suture strategy and system for surgical suture applications.
Sutures are typically the primary means of soft tissue repair in surgery and trauma. Despite their widespread use, sutures do not result in immediate sealing of approximated tissues, which can result in bacterial infection and leakage. Nonabsorbable sutures and staples can be traumatic to tissue, and the trauma can be exacerbated by their subsequent removal. Use of cyanoacrylate glues is limited because of their brittleness and toxicity. In this work, laser‐activated tissue‐integrating sutures (LATIS) are described as novel nanodevices for soft tissue approximation and repair. Incorporation of gold nanorods within fibers generated from collagen result in LATIS fibers which demonstrate robust photothermal responses following irradiation with near infrared laser light. Compared to conventional sutures, LATIS fibers result in greater biomechanical recovery of incised skin in a mouse model of skin closure after spine surgeries. Histopathology analyses show improved repair of the epidermal gap in skin, which indicate faster tissue recovery using LATIS. The studies indicate that LATIS‐facilitated approximation of skin in live mice synergizes the benefits of conventional suturing and laser‐activated tissue integration, resulting in new approaches for faster sealing, tissue repair, and healing.
Reports of immune reactions of both the immediate and delayed types due to cutaneous or systemic exposure to copper have been reviewed, in the endeavor to draw a comprehensive profile of the immunogenic potential of that metal and its compounds. Also the metal’s immunotoxic potential is briefly reviewed.
Bacterial infection often delays healing of wounded tissues and so it is essential to improve the antibacterial efficiency in situ. In this work, a hybrid hydrogel composed of 3-(trimethoxysilyl)propyl methacrylate (MPS, 97%) and mesoporous silica (mSiO2) modified CuS nanoparticles (NPs) is synthesized by radical polymerization. The materials possess excellent and controllable photothermal and photodynamic properties under 808 nm near-infrared (NIR) light irradiation as well as antibacterial efficacy of 99.80% and 99.94% against Staphylococcus aureus and Escherichia coli within 10 min, respectively. The excellent performance stems from the combined effects of hyperthermia, radical oxygen species, and released copper ions produced during NIR irradiation of CuS NPs. Moreover, the released copper ions stimulate fibroblasts proliferation and angiogenesis and the intrinsic volume transition of the hydrogel composed of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) controls the release rate of copper ions during NIR light irradiation leading to both antibacterial effects and skin tissue regeneration.
Objective:
Laser tissue soldering using photothermal solders is a technology that facilitates rapid sealing using heat-induced changes in the tissue and the solder material. The solder material is made of gold nanorods embedded in a protein matrix patch that can be placed over the tissue rupture site and heated with a laser. Although laser tissue soldering is an attractive approach for surgical repair, potential photothermal damage can limit the success of this approach. Development of predictive mathematical models of photothermal effects including cell death, can lead to more efficient approaches in laser-based tissue repair.
Methods:
We describe an experimental and modeling investigation into photothermal solder patches for sealing porcine and mouse cadaver intestine sections using near-infrared laser irradiation. Spatiotemporal changes in temperature were determined at the surface as well as various depths below the patch. A mathematical model, based on the finite element method, predicts the spatiotemporal temperature distribution in the patch and surrounding tissue, as well as concomitant cell death in the tissue is described.
Results:
For both the porcine and mouse intestine systems, the model predicts temperatures that are quantitatively similar to the experimental measurements with the model predictions of temperature increase often being within a just a few degrees of experimental measurements.
Conclusion:
This mathematical model can be employed to identify optimal conditions for minimizing healthy cell death while still achieving a strong seal of the ruptured tissue using laser soldering. Lasers Surg. Med. © 2017 Wiley Periodicals, Inc.
Drug delivery using suitable polymeric devices has gathered momentum in the recent years due to their remarkable properties. The versatility of polymeric materials makes them reliable candidates for site targeted drug release. Among them biodegradable sutures has received considerable attention because they offer great promises in the realm of drug delivery. Sutures have been found to be an effective strategy for the delivery of antibacterial agents or anti- inflammatory drugs to the surgical site. Recent developments yielded sutures with improved mechanical properties, but designing sutures with all the desirable properties is still under investigation. This review is an attempt to analyze the recent developments pertaining to biologically active sutures emphasizing their potential as drug delivery vehicle.
Introduction:
Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Areas covered: This review provides an overview of the current manufacturing processes for drug-eluting suture production and discusses their benefits and drawbacks depending on the type of drugs. The mechanical properties and the drug delivery profile of drug-eluting sutures are highlighted since these implants must fulfill both criteria. Expert opinion: For limited drug contents, melt extrusion and electrospinning are the emerging processes since the drug is added during the suture manufacture process. Advantageously, the drug release profile can be tuned by controlling the processing parameters specific to each process and the composition of the drug-containing polymer. If high drug content is targeted, the coating or grafting of a drug layer on a pre-manufactured suture allows for preservation of the tensile strength requirements of the suture.
The resistance demonstrated by many microorganisms towards conventional antibiotics have stimulated the interest in alternative antimicrobial agents and in novel approaches for prevention of infections. Silver, a natural braod-spectrum antimicrobial agent known since antiquity, has been widely employed in biomedical field due to its recognized antibacterial, antifungal and antiviral properties. In this work, antibacterial silver coatings were deposited on absorbable surgical sutures through the in situ photo-chemical deposition of silver clusters. Scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDX) and thermo-gravimetric analysis (TGA) were performed in order to investigate the presence and distribution of the silver clusters on the substrate. The amounts of silver deposited and released by the silver treated sutures were calculated through Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS), and the results were related to the biodegradation of the material. The microbiological properties and the potential cytotoxicity of the silver-treated sutures were investigated in relation with hydrolysis experiments, in order to determine the effect of the degradation on antibacterial properties and biocompatibility.
Statement of significance:
Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance in wound care management. In our study, we successfully prepared copper-containing bioactive glass/eggshell membrane (Cu-BG/ESM) nanocomposites with uniform bioactive glass nanocoatings by using pulsed laser deposition (PLD) technology. Due to the deposited Cu-BG nanocoatings on the surface of ESM, Cu-BG/ESM nanocomposites possessed significantly improved physicochemical and biological properties, including surface hydrophilicity, hardness, antibacterial ability, angiogenesis rate in vitro and wound healing quality in vivo as compared to pure ESM and BG/ESM films. Our study showed that prepared nanocoatings on Cu-BG/ESM composites offer a beneficial carrier for sustained release of Cu(2+) ions which played a key role for improving both angiogenesis and antibacterial activity. The prepared nanocomposites combined Cu-containing BG nanocoatings with ESM are a promising biomaterial for wound healing application.
Conditions for the manufacture of fibres designed for medical applications from zinc alginate and copper alginate have been developed. The high moisture absorption and anti-bacterial effects of fibres from zinc or copper alginate will allow the production of a new generation of dressing materials. At the same time, the tenacity of copper alginate fibres at a level of 21.41 cN/tex and their modified electric properties will make it possible to obtain flat textile materials designed for medical application (hospital linen, compression bandages). A comparative analysis has been carried out to assess the effects of fibre spinning conditions on the porous structure, moisture absorption and strength properties of fibres from zinc and copper alginates.
Surgical site infection and postoperative leakage are complications that may develop following colorectal surgery and result in fatal consequences. Rapid, fluid-tight wound closure through laser tissue welding (LTW) can reduce postoperative leakage and thus decrease infection. Laser tissue welding involves generation of localized heat by exposing an exogenous chromophore to near-infrared (NIR) irradiation in order to seal wounds. In this study, we generated gold nanorod (GNR)-collagen nanocomposites (NCs) for laser-facilitated welding of ruptured intestinal tissue. The fluid content, stiffness, elasticity, and laser-induced temperature response of these nanocomposites were modulated to optimize laser-induced tissue fusion and minimize tissue damage. In addition, the effect of laser operating parameters including power density, femtosecond pulsed wave (PW) or continuous wave (CW) laser, and exposure duration were all studied. Laser power density and treatment duration significantly affected the temperatures reached during welding, as well as tissue weld strength and burst pressure. CW laser was found to induce significantly higher temperatures of the nanocomposites during treatment than PW laser, but the differences in weld strength and burst pressure for the two laser types were insignificant. This suggests that PW lasers can result in robust welds while minimizing potential thermal damage compared to CW lasers. The ultimate tensile strength of welded ruptured tissue was returned to as high as 68% of the native tissue strength through laser treatment, and laser treatment with these nanocomposites restored up to 64% of native tissue leak pressure and 42% of burst pressure. To the best of our knowledge, the laser power densities used (≤2.50 W/cm2) are among the lowest reported for laser tissue welding, and the laser configuration and use require very little surgical skill. Our results indicate that GNR-collagen nanocomposites are promising photothermal biomaterials in laser tissue welding applications.
As one of the most promising medical metal implants, magnesium (Mg) or its alloys have shown significant advantages over other candidates attributed to not only their excellent biodegradability and suitable mechanical properties but also their osteopromotive effects for bone applications. Prior to approval mandated by the governmental regulatory body, the access to the medical market for Mg-based implants requires a series of testing for assurance of their safety and efficacy via preclinical evaluations and clinical tests including phases 1 and 2 evaluations, and Phase 3 of multi-center randomized double blind and placebo-controlled clinical trials. However, as the most widely used protocols for biosafety evaluation of medical devices, current ISO 10993 standards should be carefully reevaluated when directly applying them to predict potential health risks of degradable Mg based biomaterials via cytotoxicity tests due to the huge gap between in vitro and in vivo conditions. Therefore, instead of a direct adoption, modification of current ISO standards for in vitro cytotoxicity test is desirable and justified. The differences in sensitivities of cells to in vitro and in vivo Mg ions and the capability of in vivo circulation system to dilute local degradation products were fully considered to propose modification of current ISO standards. This paper recommended a minimal 6 times to a maximal 10 times dilution of extracts for in vitro cytotoxicity test specified in ISO 10993 part 5 for pure Mg developed as potential orthopaedic implants based on literature review and our specifically designed in vitro and in vivo tests presented in the study. Our work may contribute to the progress of biodegradable metals involved translational work.
Copyright © 2015. Published by Elsevier Ltd.
There is a need for better wound dressings that possess the requisite angiogenic capacity for rapid in situ healing of full-thickness skin wounds. Borate bioactive glass microfibers are showing a remarkable ability to heal soft tissue wounds but little is known about the process and mechanisms of healing. In the present study, wound dressings composed of borate bioactive glass microfibers (diameter = 0.4-1.2 μm; composition 6Na2O, 8K2O, 8MgO, 22CaO, 54B2O3, 2P2O5; mol%) doped with 0-3.0 wt.% CuO were created and evaluated in vitro and in vivo. When immersed in simulated body fluid, the fibers degraded and converted to hydroxyapatite within ∼7 days, releasing ions such as Ca, B and Cu into the medium. In vitro cell culture showed that the ionic dissolution product of the fibers was not toxic to human umbilical vein endothelial cells (HUVECs) and fibroblasts, promoted HUVEC migration, tubule formation and secretion of vascular endothelial growth factor (VEGF), and stimulated the expression of angiogenic-related genes of the fibroblasts. When used to treat full-thickness skin defects in rodents, the Cu-doped fibers (3.0 wt.% CuO) showed a significantly better capacity to stimulate angiogenesis than the undoped fibers and the untreated defects (control) at 7 and 14 days post-surgery. The defects treated with the Cu-doped and undoped fibers showed improved collagen deposition, maturity and orientation when compared to the untreated defects, the improvement shown by the Cu-doped fibers was not markedly better than the undoped fibers at 14 days post-surgery. These results indicate that the Cu-doped borate glass microfibers have a promising capacity to stimulate angiogenesis and heal full-thickness skin defects. They also provide valuable data for understanding the role of the microfibers in healing soft tissue wounds.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process.
In this work, a novel concept is introduced in drug-eluting fibres to ensure a good control of drug delivery features and wide applicability to different bioactive compounds. Composite bioactive sutures based on fibre grade poly(ε-caprolactone) (PCL) and loaded with the anti-inflammatory drug Diclofenac (Dic) or a Dic nanohybrid where the drug is intercalated in a synthetic hydrotalcite (Mg/Al hydroxycarbonate) (HT-Dic) were developed. Fibres were prepared by melt-spinning at different PCL/HT-Dic/Dic ratios and analysed in terms of morphology, mechanical properties and drug release features. Results emphasized that tensile properties of fibres are clearly affected by Dic or HT-Dic addition, while the presence of knots has limited influence on the mechanical behaviour of the sutures. Release of Dic strongly depends on how Dic is loaded in the fibre (as free or nanohybrid) whereas the combination of free Dic and HT-Dic can allow a further tuning of release profile. In vivo experiments show a reduction of inflammatory responses associated with Dic-loaded fibers. Thus, a proof of principle is provided for a novel class of bioactive sutures integrating advanced controlled-release technologies.
Approximately 1.5 million people suffer from colorectal cancer and inflammatory bowel disease in the United States. Occurrence of leakage following standard surgical anastomosis in intestinal and colorectal surgery is common, and can cause infection leading to life-threatening consequences. In this report, we demonstrate that plasmonic nanocomposites, generated from elastin-like polypeptides (ELPs) crosslinked with gold nanorods, can be used to weld ruptured intestinal tissue upon exposure to near infrared (NIR) laser irradiation. Mechanical properties of these nanocomposites can be modulated based on the concentration of gold nanorods embedded within the ELP matrix. We employed photostable, NIR-absorbing cellularized and non-cellularized GNR-ELP nanocomposites for ex vivo laser welding of ruptured porcine small intestines. Laser welding using the nanocomposites significantly enhanced the tensile strength, leakage pressure, and bursting pressure of ruptured intestinal tissue. This, in turn, provided a liquid-tight seal against leakage of luminal liquid from the intestine and resulting bacterial infection. This study demonstrates the utility of laser tissue welding using plasmonic polypeptide nanocomposites, and indicates the translational potential of these materials in intestinal and colorectal repair.
The production of monodisperse alginate hydrogel microbeads is demonstrated by using a method that combines internal gelation method with T-junction droplet formation in microfuidic devices. The use of calcium carbonate nanoparticles allows internal gelation method to be applied to micro-scale production for the first time, and microfluidic devices allow to produce microbeads with narrow size distributions. The approach allows easy control over bead size by varying flow parameters and also allows better monodispersity and control over the shape of the hydrogel beads compared to conventional external gelation methods performed in microfluidic devices. Both blank and cell encapsulating alginate hydrogel beads of various shapes were successfully produced using this approach in non-silanized/silanized poly(dimethylsiloxane) (PDMS) devices. The gelation conditions in the approach also were mild enough to encapsulate mammalian cells without loss of their viability.
Silver nanoparticles capped with sodium alginate were deposited layer-by-layer on surgical sutures and characterized for their anti-microbial activity against Staphylococcus aureus. The concentration of sodium alginate used in the synthesis step was varied from 5 mM to 0.1 mM and was found to have a major effect on the final antimicrobial activity of the fiber. The layer-by-layer deposition of the silver nanoparticles with poly (diallyldimethylammonium chloride) was first studied on glass slide by monitoring the changes in absorbance at 400 nm which correspond to the plasmon band of the silver nanoparticles. The layer-by-layer deposition process was concluded from the linear increase in film absorbance as a function of the number of deposited layers. The same deposition technique was then applied to the polyamide surgical sutures and the lowest alginate concentration produced the highest antimicrobial efficiency. These results suggest that the tuning of the capping used in the synthesis step strongly influence the later antimicrobial activity of the nanoparticles. (C) 2011 Elsevier B.V. All rights reserved.
The ultraviolet-visible absorption spectra are given for 10 nm diameter colloidal particles of 52 of the metallic elements, calculated from the optical constants of the metals by means of Mie theory. For most of the elements the spectra cover the range 200-900 nm. Well resolved absorption bands are observed for colloidal Sc, Ti, V, Y, Cd, Eu, Yb, Hg and Th as well as for colloids of Cu, Ag, Au and the s-block metals. However, for the majority of the colloidal metallic elements in this size range there is only a continuous absorption in the visible range, rising to broad and poorly resolved absorption bands in the ultraviolet near 200 nm. The difference in the way that the spectra of colloidal particles of different metals change when the particle shape is varied from spherical to spheroidal is investigated systematically in the dipole approximation. This is achieved by means of contour plots of the absorbance cross-section for the particles vs. the real and imaginary parts of the dielectric function fo
Closing lacerations in thin eyelid and periorbital skin is time consuming and requires high skill for optimal results. In this study we evaluate the outcomes after single layer closure of wounds in thin skin with a sutureless, light-activated photochemical technique called PTB.
Dorsal skin of the SKH-1 hairless mouse was used as a model for eyelid skin. Incisions (1.2 cm) were treated with 0.1% Rose Bengal dye followed by exposure to 532 nm radiation (25, 50, or 100 J/cm(2); 0.25 W/cm(2)) for PTB. Other incisions were sutured (five 10-0 monofilament), exposed only to 532 nm (100 J/cm(2)), or not treated. Outcomes were immediate seal strength (pressure causing leakage through incision of saline infused under wound), skin strength at 1, 3, and 7 days (measured by tensiometry), inflammatory infiltrate at 1, 3, and 7 days (histological assessment), and procedure time.
The immediate seal strength, as measured by leak pressure, was equivalent for all PTB fluences and for sutures (27-32 mmHg); these pressures were significantly greater than for the controls (untreated incisions or laser only treatment; P < 0.001). The ultimate strength of PTB-sealed incisions was greater than the controls at day 1 (P < 0.05) and day 3 (P < 0.025) and all groups were equivalent at day 7. Sutures produced greater inflammatory infiltrate at day 1 than observed in other groups (P = 0.019). The average procedure time for sutured closure (311 seconds) was longer than for the PTB group treated with 25 J/cm(2) (160 seconds) but shorter than the group treated with 100 J/cm(2) (460 seconds).
PTB produces an immediate seal of incisions in thin, delicate skin that heals well, is more rapid than suturing, does not require painful suture removal and is easy to apply.
Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation. Alginate hydrogels have been particularly attractive in wound healing, drug delivery, and tissue engineering applications to date, as these gels retain structural similarity to the extracellular matrices in tissues and can be manipulated to play several critical roles. This review will provide a comprehensive overview of general properties of alginate and its hydrogels, their biomedical applications, and suggest new perspectives for future studies with these polymers.
ABSTRACT Copper plays a key role in angiogenesis and in the synthesis and stabilization of extracellular matrix skin proteins, which are critical processes of skin formation. We hypothesized that introducing copper into wound dressings would enhance wound repair. Application of wound dressings containing copper oxide to wounds inflicted in genetically engineered diabetic mice (C57BL/KsOlaHsd-Lepr(db)) resulted in increased gene and in situ up-regulation of proangiogenic factors (e.g., placental growth factor, hypoxia-inducible factor-1 alpha, and vascular endothelial growth factor), increased blood vessel formation (p<0.05), and enhanced wound closure (p<0.01) as compared with control dressings (without copper) or commercial wound dressings containing silver. This study proves the capacity of copper oxide-containing wound dressings to enhance wound healing and sheds light onto the molecular mechanisms by which copper oxide-impregnated dressings stimulate wound healing.
Poor wound healing and the development of infection in incisional wounds continue to be among the most common complications of open abdominal surgery. Various bacteria may contaminate not only the tissue in the operative wound, but also the actual suture material. To prevent the contamination of suture material in surgical wounds, triclosan-coated polyglactin 910 suture materials with antibacterial activity (Vicryl plus) was developed. The aim of this study was to ascertain if the use of Vicryl plus reduced the number of wound infections after midline laparotomy comparing to polydioxanon suture (PDS II).
We performed 2,088 operations in our department between October 2004 and September 2006 via midline incision. In the first time period (TP1), a PDS II loop suture was used. In the second time period (TP2), we used Vicryl plus. All variables were recorded prospectively in a database. The primary outcome was the number of wound infections. Risk factors for poor wound healing were collected prospectively to compare the 2 groups.
Using a PDS loop suture for abdominal wall closure in TP1, 10.8% of patients with wound infections were detected. The number of patients with wound infections decreased in TP2 using Vicryl plus for abdominal wall closure to 4.9% (P < .001) despite no other changes in protocols of patient care. Other risk factors for the development of site infections were comparable in the 2 groups.
The use of antibiotic-coated loop suture for abdominal wall closure can decrease the number wound infections after abdominal surgery.
Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.
The feasibility of allogenic implants of chondrocytes in alginate gels was tested for the reconstruction in vivo of artificially full-thickness-damaged articular rabbit cartilage. The suspensions of chondrocytes in alginate were gelled by the addition of calcium chloride solution directly into the defects giving in situ a construct perfectly inserted and adherent to the subchondral bone and to the walls of intact cartilage. The tissue repair was controlled at 1, 2, 4 and 6 months after the implant by NMR microscopy, synchrotron radiation induced X-ray emission to map the sulfur of glycosaminoglycans and by histochemistry. Practically a complete repair of the defect was observed 4-6 months from the implant of the chondrocytes with the recovery of a normal tissue structure. Controls in which Ca-alginate alone was implanted developed only a fibrous cartilage.
Because copper-containing ointments are frequently used in anthroposophical medicine, a phase I trial to investigate the cutaneous absorption of copper was conducted. Sixty-one volunteers were randomized [group A: 0.4% copper (I) oxide, 13 men and 18 women (19-55 years); group B: 20% elementary copper, 11 men and 19 women (18-70 years)]. The ointment was applied over a 4-week period followed by a 4-week wash-out phase. Serum and urine copper concentrations were measured by atomic absorption spectrometry and hair copper concentration by inductive coupled plasma mass spectrometry. For statistical analysis, the Student t test for related random samples was used; alpha = 0.05 was chosen for the standard error. In group A, an increase of copper in serum and scalp hair and a decrease in urine were found in the study period. The mean serum concentration in all premenopausal women using oral contraceptives was above normal. In group B, the serum copper concentration increased significantly; in urine, it decreased, and in scalp hair, it remained stable. A higher level of serum copper was found in female volunteers using hormonal contraception. Treatment with the 2 different ointments did not cause toxic irritations on the skin, and it can therefore be deduced that the appropriate application of ointment preparations containing copper in concentrations up to 20% do not present a toxic risk.
Size-controlled small (i.e. less than 300 microm) polyelectrolyte complex gel beads are urgently desired for wide-spread application, including use in medical, pharmaceutical, and bioengineering fields. However, it was impossible to obtain smaller beads less than 300 microm with conventional apparatuses. We developed a novel microfluidics device that utilizes silicon micro-nozzle (MN) array, enabling to produce 50-200 microm calcium alginate beads with a narrow size distribution. Alginate aqueous solution was extruded through a precisely fabricated thin (30 microm x 30 microm) and short (500 microm) MN and was sheared by the viscous drag force of oil flow to form alginate droplets. Alginate droplets were immediately reacted with CaCl2 droplets at the downstream of oil flow to form calcium alginate gel beads. This device enabled us to successfully encapsulate living cells into 162 microm calcium alginate beads with maintaining viability, which was confirmed by the expression of marker protein.
Vascular endothelial growth factor (VEGF-A), a potent stimulus for angiogenesis, is up-regulated in the skin after wounding. Although studies have shown that VEGF is important for wound repair, it is unclear whether this is based solely on its ability to promote angiogenesis or if VEGF can also promote healing by acting directly on non-endothelial cell types. By immunohistochemistry and reverse transcriptase-polymerase chain reaction, expression of VEGF receptor-1 (VEGFR-1), but not VEGFR-2, was detected in murine keratinocytes during wound repair and in normal human epidermal keratinocytes (NHEKs). The presence of VEGF receptors on NHEKs was verified by binding studies with 125I-VEGF. In vitro, VEGF stimulated the proliferation of NHEKs, an effect that could be blocked by treatment with neutralizing VEGFR-1 antibodies. A role for VEGFR-1 in keratinocytes was also shown in vivo because treatment of excisional wounds with neutralizing VEGFR-1 antibodies delayed re-epithelialization. Treatment with anti-VEGFR-1 antibodies also reduced the number of proliferating keratinocytes at the leading edge of the wound, suggesting that VEGF sends a proliferative signal to these cells. Together, these data describe a novel role for VEGFR-1 in keratinocytes and suggest that VEGF may play several roles in cutaneous wound repair.
Fibers of alginate and polyethylene glycol (PEG), with salicylic acid (SA) as model drug incorporated in different concentrations, were obtained by spinning their solution through a viscose-type spinneret into a coagulating bath containing aqueous CaCl(2) and ethanol. Chemical, morphological, and mechanical properties characterization were carried out, as well as the studies of the factors that influence the drug releasing from alginate/PEG fibers. These factors included the component ratio of alginate and PEG, the loaded amount of SA, the pH, and the ionic strength of the release solution and others. The best values of the tensile strength at 13.41 cN/tex and breaking elongation at 23.13% of blend fibers were obtained when the PEG content was 5 wt %; the water swelling ratio (WSR) of blend fibers increased as the composition of PEG was raised. The results of controlled release tests showed that the amount of SA released increased with an increase in the proportion of PEG present in the fiber. Moreover, the release rate of drug decreased as the amount of drug loaded in the fiber increased, but the cumulative release amount is increasing. The alginate/PEG fibers were also sensitive to pH and ionic strength. For pH 7.4 the drug release was faster compared to pH 1.0, being simultaneously accelerated by a higher ionic strength. All the results indicated that the alginate/PEG fiber was potentially useful in drug delivery systems.
Copper is an essential trace element involved in numerous human physiological and metabolic processes. It plays a key role in many of the processes that together comprise wound healing, including induction of endothelial growth factor, angiogenesis and expression and stabilization of extracellular skin proteins. We hypothesize that in individuals with diabetic ulcers, decubitus, peripheral vascular, or other wounds which might have compromised circulation to the wound site, that part of the incapacity of the wounds to heal is due to low local copper levels. Contamination of wounds is also an important factor causing impaired wound healing. Importantly, copper has potent broad biocidal properties. In contrast, the risk of adverse skin reactions due to exposure to copper is extremely low. We thus hypothesize that introducing copper into wound dressings would not only reduce the risk of wound and dressing contamination, as silver does but, more importantly, would stimulate faster wound repair directly. This would be done by the release of copper from the wound dressings directly into the wound site inducing angiogenesis and skin regeneration.