Stretchable Functional Nanocomposites for Soft Implantable Bioelectronics.

Material advances in soft bioelectronics, particularly those based on stretchable nanocomposites─functional nanomaterials embedded in viscoelastic polymers with irreversible or reversible bonds─have driven significant progress in translational medical device research. The unique mechanical properties inherent in the stretchable nanocomposites enable stiffness matching between tissue and device, as well as its spontaneous mechanical adaptation to in vivo environments, minimizing undesired mechanical stress and inflammation responses. Furthermore, these properties allow percolative networks of conducting fillers in the nanocomposites to be sustained even under repetitive tensile/compressive stresses, leading to stable tissue-device interfacing. Here, we present an in-depth review of materials strategies, fabrication/integration techniques, device designs, applications, and translational opportunities of nanocomposite-based soft bioelectronics, which feature intrinsic stretchability, self-healability, tissue adhesion, and/or syringe injectability. Among many, applications to brain, heart, and peripheral nerves are predominantly discussed, and translational studies in certain domains such as neuromuscular and cardiovascular engineering are particularly highlighted.

Light-Activated Chemically Reactive Fibrous Patch Revolutionizes Wound Repair Through the Prevention of Postoperative Adhesion.

A light-activated chemically reactive fibrous patch (ChemPatch) with tissue adhesion and wound healing activity was developed for preventing postoperative peritoneal adhesion. ChemPatch was constructed by an integrative electrospinning fabrication strategy, generating multifunctional PCL-NHS fibers encapsulating antioxidant curcumin and MnO2 nanoparticles. ChemPatch exhibited excellent photothermal conversion, which not only reformed the physical state to match the tissue but also improved conjugation between ChemPatch and tissues, allowing for strong attachment. Importantly, ChemPatch possessed good antioxidant and radical scavenging activity, which protected cells in an oxidative microenvironment and improved tissue regeneration. Particularly, ChemPatch acted as a multifunctional barrier and could not only promote reepithelialization and revascularization in wound defect model but simultaneously ameliorate inflammation and prevent postoperative peritoneal adhesion in a mouse cecal defect model. Thus, ChemPatch represents a dual-active bioadhesive barrier for reducing the incidence and severity of peritoneal adhesions.

Adhesive Composite Microspheres with Dual Antibacterial Strategies for Infected Wound Healing.

Skin damage and infection pose a severe challenge to human health. Construction of a novel versatile dressing with good anti-infection and healing-promoting abilities is greatly expected. In this paper, nature-source-based composite microspheres with dual antibacterial mechanisms and bioadhesive features by microfluidics electrospray for infected wound healing is developed. The microspheres enable sustained release of copper ions, which not only show long-term antibacterial properties, but also play important role in wound-healing-related angiogenesis. Additionally, the microspheres are coated with polydopamine via self-polymerization, which renders the microspheres adhesive to the wound surface, and further enhance the antibacterial ability through photothermal energy conversion. Based on the dual antibacterial strategies provided by copper ions and polydopamine as well as the bioadhesive property, the composite microspheres exhibit excellent anti-infection and wound healing performances in a rat wound model. These results, along with the nature-source-based composition and biocompatibility, indicate the great potential of the microspheres in clinical wound repair.

Thermoreversible Tissue Adhesion with Hydrogel Through a Topological Entanglement Approach.

Achieving thermoreversible adhesion between hydrogel and living tissues in a facile way is challenging. Existing strategies bring difficulty to the chemical design and synthesis of hydrogels. Herein, an approach to achieve tough thermoreversible tissue adhesion with hydrogel is proposed, which uses a polymer solution with heat-induced sol-gel transition as the interfacial polymer matrix, with no chemical design required for the hydrogel network. When the interfacial polymer matrix is introduced to the interface of the hydrogel and living tissues, it can gelate in situ within the substrate networks under a temperature stimulus, and topologically entangle with the preexisting networks of the substrates, which generates a strong adhesion. By triggering with another temperature stimulus, the newly formed network dissociates to realize an easy detachment. Thermoreversible adhesion is demonstrated between polyacrylamide hydrogel and various porcine tissues as examples, and the mechanism of this adhesion strategy is studied by varying various influence factors. A theoretical model that can fit and predict the effects of different parameters on the adhesion energies is also established. This adhesion strategy based on topological entanglement among a thermoreversible polymer system and the substrates may broaden the achieving methods of thermoreversible tissue adhesion.

Rosmarinic Acid-Grafted Dextran/Gelatin Hydrogel as a Wound Dressing with Improved Properties: Strong Tissue Adhesion, Antibacterial, Antioxidant and Anti-Inflammatory.

Designing a strong tissue adhesive and multifunctional hydrogel dressing for various skin injuries is still a significant challenge. Based on the bioactive activities of rosmarinic acid (RA) and its catechol structure being similar to dopamine, RA-grafted dextran/gelatin hydrogel (ODex-AG-RA) was designed and systemically characterized in this study. The ODex-AG-RA hydrogel exhibited excellent physicochemical properties, including fast gelation time (61.6 ± 2.8 s), strong adhesive strength (27.30 ± 2.02 kPa) and enhanced mechanical properties (1.31 × 104 Pa of G'). The examination of hemolysis and co-culturing with L929 cells showed the strong in vitro biocompatibility of ODex-AG-RA hydrogels. The ODex-AG-RA hydrogels exhibited a 100% mortality rate against S. aureus and at least 89.7% against E. coli in vitro. In vivo evaluation for efficacy in skin wound healing was carried out in a rat model of full-thickness skindefect. The amount of collagen deposition and CD31 on wounds in the two ODex-AG-RA-1 groups on day 14 was 4.3 times and 2.3 times of that in the control group, respectively. Furthermore, the mechanism of ODex-AG-RA-1 for promoting wound healing was proved to be related to its anti-inflammatory properties by adjusting the expression of inflammatory cytokines (TNF-α and CD163) and reducing the level of oxidative stress (MDA and H2O2). Overall, this study demonstrated the wound-healing efficacy of RA-grafted hydrogels for the first time. ODex-AG-RA-1 hydrogel, due to its adhesive, anti-inflammatory, antibacterial and antioxidative activities, was a promising candidate as a wound dressing.

Engineering Bio-Adhesives Based on Protein-Polysaccharide Phase Separation.

Glue-type bio-adhesives are in high demand for many applications, including hemostasis, wound closure, and integration of bioelectronic devices, due to their injectable ability and in situ adhesion. However, most glue-type bio-adhesives cannot be used for short-term tissue adhesion due to their weak instant cohesion. Here, we show a novel glue-type bio-adhesive based on the phase separation of proteins and polysaccharides by functionalizing polysaccharides with dopa. The bio-adhesive exhibits increased adhesion performance and enhanced phase separation behaviors. Because of the cohesion from phase separation and adhesion from dopa, the bio-adhesive shows excellent instant and long-term adhesion performance for both organic and inorganic substrates. The long-term adhesion strength of the bio-glue on wet tissues reached 1.48 MPa (shear strength), while the interfacial toughness reached ~880 J m-2. Due to the unique phase separation behaviors, the bio-glue can even work normally in aqueous environments. At last, the feasibility of this glue-type bio-adhesive in the adhesion of various visceral tissues in vitro was demonstrated to have excellent biocompatibility. Given the convenience of application, biocompatibility, and robust bio-adhesion, we anticipate the bio-glue may find broad biomedical and clinical applications.

Effect of the platelet-rich plasma covering of polypropylene mesh on oxidative stress, inflammation, and adhesions.

INTRODUCTION AND HYPOTHESIS: Polypropylene mesh (PPM) is often used for urogynecological repair; however, it can cause complications. An approach to reduce complications is to coat PPM with anti-inflammatory and wound-healing molecules. Platelet-rich plasma (PRP) is inexpensive and improves wound healing. Therefore, we evaluated whether covering PPM with PRP could reduce inflammation, adhesion, and oxidative stress (OS) in rabbits. METHODS: The primary objective was to evaluate OS, and the secondary objectives were to evaluate inflammation and adhesion. PRP-coated PPM was implanted on the right side of the abdominal cavity of 12 female New Zealand rabbits, in the interface between the hypodermis and peritoneum. An uncoverated PPM was implanted in the other side. Twelve rabbits served as the sham group; all animals were euthanized after 30 or 60 days. Inflammatory parameters were myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activities. OS was evaluated by measuring the ferric-reducing antioxidant power, the free-radical-reducing ability of 3-ethylbenzothiazoline-6-sulfonic acid [2,2'-azino-bis (ABTS)], reduced glutathione levels, and superoxide anion production. Adhesion was measured using tenacity and Diamond scales (the latter of which grades adhesions according to their extent) Inflammation and OS were analyzed by analysis of variance (ANOVA), followed by Tukey's test. The Mann-Whitney test was used to evaluate adhesions, and analysis of the sham group was conducted using Kruskal-Wallis test. RESULTS: No significant differences were observed in parameters of adhesions. After 60 days, PRP-coverated PPM presented a decrease in MPO and NAG activities. Furthermore, decreased OS and increased antioxidant levels were observed in PRP-coverated PPM samples. CONCLUSIONS: The reduction of OS and inflammatory responses indicates that PRP-covered PPM is a promising therapeutic approach.

Nonlocal and local models for taxis in cell migration: a rigorous limit procedure.

A rigorous limit procedure is presented which links nonlocal models involving adhesion or nonlocal chemotaxis to their local counterparts featuring haptotaxis and classical chemotaxis, respectively. It relies on a novel reformulation of the involved nonlocalities in terms of integral operators applied directly to the gradients of signal-dependent quantities. The proposed approach handles both model types in a unified way and extends the previous mathematical framework to settings that allow for general solution-dependent coefficient functions. The previous forms of nonlocal operators are compared with the new ones introduced in this paper and the advantages of the latter are highlighted by concrete examples. Numerical simulations in 1D provide an illustration of some of the theoretical findings.

Multifunctional Hydrophobized Microparticles for Accelerated Wound Healing after Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection (ESD) provides strong therapeutic benefits for early gastrointestinal cancer as a minimally invasive treatment. However, there is currently no reliable treatment to prevent scar contracture resulting from ESD which may lead to cicatricial stricture. Herein, a multifunctional colloidal wound dressing to promote tissue regeneration after ESD is demonstrated. This sprayable wound dressing, composed of hydrophobized microparticles, exhibits the multifunctionality necessary for wound healing including tissue adhesiveness, blood coagulation, re-epithelialization, angiogenesis, and controlled inflammation based on hydrophobic interaction with biological systems. An in vivo feasibility study using swine gastric ESD models reveals that this colloidal wound dressing suppresses fibrosis and accelerates wound healing. Multifunctional colloidal and sprayable wound dressings have an enormous therapeutic potential for use in a wide range of biomedical applications including accelerated wound healing after ESD, prevention of perforation, and the treatment of inflammatory diseases.

Marine-Inspired Polymers in Medical Adhesion.

Medical adhesives that are strong, easy to apply and biocompatible are promising alternatives to sutures and staples in a large variety of surgical and clinical procedures. Despite progress in the development and regulatory approval of adhesives for use in the clinic, adhesion to wet tissue remains challenging. Marine organisms have evolved a diverse set of highly effective wet adhesive approaches that have inspired the design of new medical adhesives. Here we provide an overview of selected marine animals and their chemical and physical adhesion strategies, the state of clinical translation of adhesives inspired by these organisms, and target applications where marine-inspired adhesives can have a significant impact. We will focus on medical adhesive polymers inspired by mussels, sandcastle worms, and cephalopods, emphasize the history of bioinspired medical adhesives from the peer reviewed and patent literature, and explore future directions including overlooked sources of bioinspiration and materials that exploit multiple bioinspired strategies.

Photochemical Tissue Bonding Technique for Improving Healing of Hand Tendon Injury.

PURPOSE: We utilized a novel approach of combined photochemical tissue bonding (PTB) and human amniotic membrane (HAM) to improve hand tendon repair and also evaluated its efficacy. METHODS: Subei chickens underwent surgical transection of the flexor digitorum profundus tendons and repair by (1) SR (standard Kessler suture; n = 24; 6-0 prolene) and (2) HAM/PTB (n = 24), where a section of HAM was stained with 0.1% Rose Bengal, wrapped around the ruptured tendon and bonded with 532 nm light (0.5 W/cm2, 200 J/cm2). Total active motion, gross appearance, extent of adhesion formation, biochemical properties, and inflammatory cells of the repaired tendon were evaluated on days 3, 7, 14, and 28 postoperatively. RESULTS: PTB strongly bonded HAM with flexor digitorum profundus tendon surface. No significant difference was observed between the tensile properties of either group on all postoperative time points. The joint activities and the adhesion formation levels were significantly better in the HAM/PTB group compared with those in the SR group on day 14. Histological examination revealed drastically reduced number of inflammatory cells in the HAM/PTB group than in the SR group on days 7 and 14 after surgery. CONCLUSIONS: These findings revealed that PTB sealing of HAM around the tendon repair site provided considerable benefits for hand tendon repair by eliminating technical difficulties and obvious contraindications. Thus, this novel procedure has considerable benefits in repairing hand tendon damage.

[Advances in aquatic bio-inspired medical adhesives].

In recent years, due to the dramatic increase in the number of surgical operations, there has been a clinically significant increase in the demand for medical adhesives capable of cohesion in a moist environment that can overcome blood or tissue fluids in vivo. As the understanding of the mechanisms and key elements of natural adhesion to aquatic organisms continues to develop, a variety of medical adhesives have been developed by mimicking adhesion procedures or utilizing key functional groups. This article will review the classification, adhesion mechanism, use, research progress and development prospects of biomedical adhesives inspired by aquatic organisms octopus and mussels.

[Application of adhesive compositions in surgery (in Russian only)]. / Primenenie kleevykh kompozitsii v khirurgii.

New adhesive compositions will almost completely prevent leakage of surgical sutures and undue tissue damage, improve healing and postoperative rehabilitation. At present time there is no universal type of bioadhesives that is suitable for all tissues and types of sutures because of various surgeries and their specificity. The article describes the advantages and disadvantages of all common types of bioadhesives, as well as the ways to overcome their disadvantages.

Incidence of adhesions and maternal and neonatal morbidity after repeat cesarean section.

PURPOSE OF INVESTIGATION: We investigated the effect of repeat cesarean sections (CSs) and intra-abdominal adhesions on neonatal and maternal morbidity. MATERIALS AND METHODS: We analyzed intra-abdominal adhesions of 672 patients. RESULTS: Among the patients, 173, 206, 151, and 142 underwent CS for the first, second, third, and fourth time or more, respectively. There were adhesions in 393 (58.5 %) patients. Among first CSs, there were no adhesions, the rate of maternal morbidity [Morales et al. (Am J Obstet Gynecol 196(5):461, 2007)] was 26 %, and the rate of neonatal morbidity (NM) was 35 %. Among women who have history of two CSs, the adhesion rate was 66.3 %, the adhesion score was 2.05, MM was 14 %, and NM was 21 %. Among third CSs, these values were 82.1, 2.82, 23, and 14 %, respectively. Among women who have history of four or more CSs, these values were 92.2, 4.72, 31.7, and 18 %, respectively. Adhesion sites and dense fibrous adhesions increased parallel to the number of subsequent CSs. Increased adhesion score was associated with 1.175-fold higher odds of NM and 1.29-fold higher odds of MM. The rate of NM was eightfold higher in emergency-delivered newborns (emergency: 39.4, 40 %; elective: 4.9 %). MM was 20 and 26 % for elective and emergency CSs, respectively. CONCLUSIONS: Emergency operations and adhesions increased complications.

Evaluation of composition effects on the tissue-adhesive, mechanical and physical properties of physically crosslinked hydrogels based on chitosan and pullulan for wound healing applications.

Tissue adhesion of hydrogels plays an important role in wound healing, which can improve the efficiency of wound treatment, stop bleeding, facilitate tissue growth and wound closure. However, most non-covalent crosslinked hydrogels have weak tissue adhesion and rheological properties. Furthermore, it remains a challenge to synthesize a fully physically crosslinked hydrogel with good rheological properties without compromising its tissue adhesion strength. In this paper, a physically crosslinked hydrogel was developed from a mixture of chitosan and pullulan in different polymer volume ratios using aqueous NaOH. Fourier transform infrared spectroscopy, scanning electron microscopy, thermal analysis, rheological and lap shear tests were used to evaluate the influence of polymer volume ratios on the rheological, and tissue adhesive properties of the hydrogels. It was found that the hydrogels possessed high tissue adhesive strength ranging from 18.0 ± 0.90 to 49.0 ± 2.45 kPa and good storage moduli up to 5.157 ± 1.062 kPa. Gentamicin was incorporated into this polymer matrix and the release profile was investigated. The ratio of chitosan and pullulan to obtain hydrogels with optimum viscoelastic and tissue adhesive properties was identified to be CS/PUL 2:1. These results indicated that the synthesized hydrogels can be potential materials for biomedical applications such as medical adhesives and wound dressings.

Killing Two Birds with One Stone: Shape-Memory Cryogels for Hemostasis and Wound Repair.

The development of shape-memory hemostatic agents is crucial for the treatment of deep incompressible bleeding tissue. However, there are few reports on biomaterials that can monitor bacterial infection at the wound site in real time following hemostasis and effectively promote repair. In this study, we propose a multifunctional QCSG/FLZ cryogel composed of glycidyl methacrylate-functionalized quaternary chitosan (QCSG), fluorescein isothiocyanate (FITC), and a lysozyme (LYZ)-modified zeolitic imidazolate framework (ZIF-8) for incompressible bleeding tissue hemostasis and wound repair. QCSG/FLZ cryogels possess interconnected microporous structure and enhanced mechanical properties, allowing them to be molded into different shapes for effective hemostasis in deep incompressible wounds. Furthermore, the fluorescence quench signal of QCSG/FLZ cryogels enables timely monitoring of bacterial infection when wound triggers infection. Meanwhile, the acidic microenvironment of bacterial infection induces structural lysis of ZIF-8, releasing LYZ and Zn2+, which effectively kill bacteria and accelerate wound repair. In conclusion, our study not only provides potential application of QCSG/FLZ cryogels for hemostasis in deep incompressible wounds but promisingly promotes the development of a tissue repair technique.

Robust aortic media adhesion using hydrophobically modified Alaska pollock gelatin-based adhesive for aortic dissections.

Type-A aortic dissection is an acute injury involving the delamination of the aorta at the parts of the aortic media. Aldehyde crosslinker-containing glues have been used to adhere to the media of the dissected aorta before joining an artificial graft. These glues effectively adhere to the aortic media; however, they show low biocompatibility due to the release of aldehyde compounds. In this study, we report innovative adhesives based on hydrophobically modified Alaska pollock gelatin (hm-ApGltn) with different alkyl or cholesteryl (Chol) groups that adhere to the media of the dissected aorta by combining hm-ApGltns with a biocompatible crosslinker, pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. The modification of alkyl or Chol groups contributed to enhanced adhesion strength between porcine aortic media. The adhesion strength increased with increasing modification ratios of alkyl groups from propanoyl to dodecanoyl groups and then decreased at a modification ratio of ~20 mol %. Porcine aortic media adhered using 7.5Chol-ApGltn adhesive showed stretchability even when expanded and shrunk vertically by 25% at least five times. Hm-ApGltn adhesives subcutaneously injected into the backs of mice showed no severe inflammation and were degraded during the implantation period. These results indicated that hm-ApGltn adhesives have potential applications in type-A aortic dissection.

Effect of Silica Nanoparticle Treatment on Adhesion between Tissue-like Substrates and In Vivo Skin Wound Sealing.

Silica nanoparticles are innovative solutions of surgical glue that can readily adhere to various tissue-like substrates without the need for time-consuming chemical reactions or ultraviolet irradiation. Herein, 10 nm-sized silica nanoparticle (SiNP10) treatment exhibited maximum adhesion strength in the porcine heart tissue model, which was approximately 7.15 times higher than that of the control group of non-treatment. We assessed the effects of silica nanoparticle treatment on in vivo skin wounds by scoring tissue adhesion and inflammation using histological images. Compared to the commercial cyanoacrylate skin adhesive (Dermabond), suppression of inflammatory cytokine levels in the incision wound skin was observed. We further quantified the expression of angiogenic growth factors and connective tissue formation-related proteins. On day 5 after wound closing treatment, the expression levels of PDGF-BB growth factor were significantly higher in SiNP10 treatment (0.64 ± 0.03) compared to Dermabond (0.07 ± 0.05). This stimulated angiogenesis and connective tissue formation in the skin of the incision wound may be associated with the promoting effects of SiNP10 treatment on wound closure and tissue adhesion.

Epidermal growth factor-loaded, dehydrated physical microgel-formed adhesive hydrogel enables integrated care of wet wounds.

Integrated wound care, a sequential process of promoting wound hemostasis, sealing, and healing, is of great clinical significance. However, the wet environment of wounds poses formidable challenges for integrated care. Herein, we developed an epidermal growth factor (EGF)-loaded, dehydrated physical microgel (DPM)-formed adhesive hydrogel for the integrated care of wet wounds. The DPMs were designed using the rational combination of hygroscopicity and reversible crosslinking of physical hydrogels. Unlike regular bioadhesives, which consider interfacial water as a barrier to adhesion, DPMs utilize water to form desirable adhesive structures. The hygroscopicity allowed the DPMs to absorb interfacial water and subsequently, the interfacial adhesion was realized by the interactions between tissue and DPMs. The reversible crosslinks further enabled DPMs to integrate into hydrogels (DPM-Gels), thus achieving wet adhesion. Importantly, the water-absorbing gelation mode of DPMs enabled facile loading of biologically active EGF to promote wound healing. We demonstrated that the DPM-Gels possessed wet tissue adhesive performance, with about 40 times the wet adhesive strength of fibrin glue and about 4 times the burst pressure of human blood pressure. Upon application at the injury site, the EGF-loaded DPM-Gels sequentially promoted efficient wound hemostasis, stable sealing, and quick healing, achieving integrated care of wet wounds.

Sprayable tissue adhesive microparticle-magnetic nanoparticle composites for local cancer hyperthermia.

Incomplete removal of early-stage gastrointestinal cancers by endoscopic treatments often leads to recurrence induced by residual cancer cells. To completely remove or kill cancer tissues and cells and prevent recurrence, chemotherapy, radiotherapy, and hyperthermia using biomaterials with drugs or nanomaterials are usually administered following endoscopic treatments. However, there are few biomaterials that can be applied using endoscopic devices to locally kill cancer tissues and cells. We previously reported that decyl group-modified Alaska pollock gelatin-based microparticles (denoted C10MPs) can adhere to gastrointestinal tissues under wet conditions through the formation of a colloidal gel driven by hydrophobic interactions. In this study, we combined C10MPs with superparamagnetic iron oxide nanoparticles (SPIONs) to develop a sprayable heat-generating nanomaterial (denoted SP/C10MP) for local hyperthermia of gastrointestinal cancers. The rheological property, tissue adhesion strength, burst strength, and underwater stability of SP/C10MP were improved through decyl group modification and SPION addition. Moreover, SP/C10MP that adhered to gastrointestinal tissues formed a colloidal gel, which locally generated heat in response to an alternating magnetic field. SP/C10MP successfully killed cancer tissues and cells in colon cancer-bearing mouse models in vitro and in vivo. Therefore, SP/C10MP has the potential to locally kill residual cancer tissues and cells after endoscopic treatments.