Isoreactive Manipulation of Bioadhesive Polymers Impacts Tissue-Specific Interactions

Bioadhesive polymers can serve as surgical sealants with a wide range of potential clinical applications, including augmentation of wound closure and acute induction of hemostasis. Key determinants of sealant efficacy include the strength and duration of tissue-material adhesion, as well as material biocompatibility. Canonical bioadhesive materials, however, are limited by a tradeoff among performance criteria that is largely governed by the efficiency of tissue-material interactions. In general, increasingly bioreactive materials are endowed with greater bioadhesive potential and protracted residence time, but incite more tissue damage and localized inflammation. One emergent strategy to improve sealant clinical performance is application-specific material design, with the goal of leveraging both local soft tissue surface chemistry and environmental factors to promote adhesive tissue-material interactions. We hypothesize that copolymer systems with equivalent bioreactive group densities (isoreactive) but different amounts/oxidation states of constituent polymers will exhibit differential interactions across soft tissue types. We synthesized an isoreactive family of aldehyde-mediated co-polymers, and subjected these materials to physical (gelation time), mechanical (bulk modulus and adhesion strength), and biological (in-vitro cytotoxicity and in-vivo biocompatibility) assays indicative of sealant performance. Results show that while bioadhesion to a range of soft tissue surfaces (porcine aortic adventitia, renal artery adventitia, renal cortex, and pericardium) varies with isoreactive manipulation, general indicators of material biocompatibility remain constant. Together these findings suggest that isore-active tuning of polymeric systems is a promising strategy to circumvent current challenges in surgical sealant applications.

Natural polymer-derived photocurable bioadhesive hydrogels for sutureless keratoplasty

Keratoplasty is the gold standard treatment for visual impairment caused by corneal damage.The use of suturing as the bonding method is the source of many complications following keratoplasty.Currently available corneal adhesives do not have both adequate adhesive strength and acceptable biocompatibility.Herein,we developed a photocurable bioadhesive hydrogel which was composed of gelatin methacryloyl and oxidized dextran for sutureless keratoplasty.The bioadhesive hydrogel exhibited high light transmittance,resistance to enzymatic degradation and excellent biocompatibility.It also had higher adhesive strength than commercial adhesives(fibrin glue).In a rabbit model of lamellar keratoplasty,donor corneal grafts could be closely bonded to the recipient corneal bed and remained attached for 56 days by using of this in situ photopolymerized bioadhesive hydrogel.The operated cornea maintained transparent and noninflamed.Sutureless keratoplasty using bioadhesive hydrogel allowed rapid graft re-epithelialization,typically within 7 days.In vivo confocal microscopic and histological evaluation of the operated cornea did not show any apparent abnormalities in terms of corneal cells and ultrastructure.Thus,this bioadhesive hydrogel is exhibited to be an appealing alternative to sutures for keratoplasty and other corneal surgeries.

Design and development of novel bioadhesive niosomal formulation for the transcorneal delivery of anti-infective agent:In-vitro and ex-vivo investigations

Gatifloxacin eye drops are frequently used in eye infections.However such formulations have a major drawback i.e.short duration of action and usually require 4e6 times installations daily.A chitosan coated niosomal formulation of gatifloxain was purposed to show a longer retention time on eyes and subsequent reduction in dosing frequency.Vesicles were prepared by solvent injection method using cholesterol and Span-60.An extensive optimization of formulation was done using different ratios of cholesterol,Span-60 and drug,revealed NS60-5(cholesterol:span-6050:50 and drug content of 20 mg)to be the optimized niosome formulation.NS60-5 had shown a highest entrapment efficiency of 64.9±0.66%with particle size 213.2±1.5 nm and zeta potential
34.7±2.2 mV.Optimized niosomes were also coated with different concentrations of chitosan and evaluated.Permeation studies had revealed that optimized niosomes(86.77±1.31%)had increased the transcorneal permeation of Gatifloxacin more than two fold than simple drug solution(37.19±1.1%).Longer retention potential of the coated niosomes was further verified by fluorescence microscopy.Study revealed that simple dye solution got easily washed out with in 6 h.The uncoated niosomes(NS60-5)showed a longer retention(more than 6 h),which was further enhanced in case of coated niosomes i.e.CNS60-1(more than 12 h).Antimicrobial studies had shown the better efficacy of CNS60-1(zone of inhibition)when compared to marketed formulation.The final chitosan formulation was found to have shown better ocular tolerability as demonstrated by corneal hydration test histopathology investigations.

The development of polycarbophil as a bioadhesive material in pharmacy

Polycarbophil(PCP),a kind of pharmaceutical polymers with superior bioadhesive properties has been widely used in the field of controlled drug delivery systems.It could be used as a highly efficient thickener,bioadhesive agent,suspending aid and emulsion stabilizer when dispersed in water or other polar solvents.These exceptional utilities of the polymers result from their hydrophilic nature.Hydrogen bonding plays an important role in most adhesion behaviours and becomes the main adhesion force.This paper reviews the applications of PCP in pharmacy over the past decades,and clarifies its unique advantages in the bioadhesive formulations.After an introduction discussing its structural characteristics and action mechanism,the focus turned to the description of its available applications in detail with particular emphasis on the ocular,nasal,vagina and oral drug delivery systems.The other less developed formulations are also described,including the buccal and the transdermal delivery systems.

Enhancing the separation performance by introducing bioadhesive bonding layer in composite pervaporation membranes for ethanol dehydration

A high performance composite membrane was prepared under the inspiration of bioadhesion principles for pervaporative dehydration of ethanol.Chitosan(CS)and polyacrylonitrile(PAN)ultrafiltration membranes were used as the active layer and the support layer,respectively.Guar gum(GG),a natural bioadhesive,was introduced as the intermediate bonding layer to improve the separation performance and stability of the fabricated CS/GG/PAN composite membranes.The contact angle of the GG layer was just between those of the CS layer and the PAN layer,minimizing the difference of hydrophilicity between the active layer and the support layer.The peeling strength of the composite membrane was significantly enhanced after the introduction of the GG layer.The effects of preparation conditions and operation conditions including GG concentration,operating temperature and ethanol concentration in feed on the pervaporation performance were investigated.The as-fabricated CS/GG/PAN composite membrane showed the optimum performance with a permeation flux of up to804 g·m-2·h-1and a separation factor higher than 1900.Besides,the composite membranes exhibited a desirable long-term operational stability.

Hydrogel bioadhesives harnessing nanoscale phase separation for Achilles tendon repairing

Repairing Achilles tendon has emerged as a long-standing challenge in the orthopaedic surgeries.Although suture is the gold standard for re-attaching and repairing the fractured Achilles tendons in clinical surgeries,it is still subjected to numerous adverse side-effects,including chronic inflammatory,tendon tissue re-rupture,scar formation,and post-surgical peritendinous adhesion.In this work,we develop a class of hydrogel bioadhesives with tailored nanoscale phase separation for Achilles tendon repairing.To address the existing limitations of sutures,our hydrogel bioadhesives encompass three core functionalities:(i)instant and tough adhesion to Achilles tendon tissues,(ii)extraordinary long-term adhesion robustness under wet and dynamic in vivo conditions,and(iii)anti-postsurgical peritendinous adhesion.Combining our hydrogel bioadhesives with sutures,such kind of integrated approach enables a conformable yet robust biointerface with the tendon tissues,and prevents the fibroblast migration and formation of connective tissues,thus facilitating the tendon repairing.The hydrogel bioadhesives reported here open up new opportunities for the repairing of fractured Achilles tendons in diverse and complicated clinical scenarios.

Accelerated Curing Speed of Ethyl a-Cyanoacrylate by Polymer with Catecholamine Groups

Four kinds of poly（ethylene glycol） （PEG） derivatives with the similar backbone and different side groups have been synthesized successfully. When both catecholamine and double bond are tethered to polymer backbone, i.e., the PEG backbone, simultaneously, the polymer can accelerate the curing speed of ethyl a-cyanoacrylate （commer- cially available as 502） greatly under the same conditions （the curing time of such system is no more than 5 s）. Probably this is due to the autoxidation of catecholamines. Through the redox-cycling, catecholamines can produce, collect free radicals, and thus initiate the free radical polymerization. Due to the fast-curing of such material when mixed with a-cyanoacrylate, we could design and develop a new bicomponent super bioglue used in the dentistry or other bioenvironment requiring super fast settlement for further surgical operations.

Combination of biodegradable hydrogel and antioxidant bioadhesive for treatment of breast cancer recurrence and radiation skin injury

Postoperative radiotherapy is the standard method for inhibition of breast cancer recurrence and metastasis,whereas radiation resistant and ineluctable skin radiation injury are still key problems encountered in the prognosis of breast cancer.Herein,we design an internally implantable biodegradable hydrogel and extracutaneously applicable antioxidant bioadhesive to concurrently prevent postoperative tumor recurrence and radioactive skin injury after adjuvant radiotherapy.The biodegradable silk fibroin/perfluorocarbon hydrogel loading doxorubicin(DOX)formed by consecutive ultrasonication-inducedβ-sheets-crosslinked amphiphilic silk fibroin/perfluorocarbon/DOX nanoemulsion,exhibits continuous release of oxygen in physiological environment to improve hypoxia and sensitivity of radiotherapy,as well as simultaneous release of DOX to finally achieve effective anti-cancer effect.A stretchable bioadhesive is fabricated by copolymerization ofα-thioctic acid and N,N-diacryloyl-L-lysine,and gold nanorods and gallic acid are loaded into the bioadhesive to afford gentle photothermal therapy and antioxidant functions.The near-infrared light-induced controlled release of gallic acid and mild photothermal therapy can efficiently eliminate excess free radicals generated by radiotherapy and promote radioactive wound healing.Ultimately,in vivo animal studies substantiate the efficacy of our methodology,wherein the post-tumor resection administration of hydrogel and concomitant application of an antioxidant bioadhesive patch effectively inhibit tumor recurrence and attenuate the progression of skin radiation damage.

An injectable and coagulation-independent Tetra-PEG hydrogel bioadhesive for post-extraction hemostasis and alveolar bone regeneration

Effective control of post-extraction hemorrhage and alveolar bone resorption is critical for successful extraction socket treatment,which remains an unmet clinical challenge.Herein,an injectable Tetra-PEG hydrogel that possesses rapid gelation,firm tissue adhesion,high mechanical strength,suitable degradability,and excellent biocompatibility is developed as a sutureless and coagulation-independent bioadhesive for the management of extraction sockets.Our results demonstrate that the rapid and robust adhesive sealing of the extraction socket by the Tetra-PEG hydrogel can provide reliable protection for the underlying wound and stabilize blood clots to facilitate tissue healing.In vivo experiments using an anticoagulated rat tooth extraction model show that the hydrogel significantly outperformed clinically used cotton and gelatin sponge in hemostatic efficacy,wound closure,alveolar ridge preservation,and in situ alveolar bone regeneration.Histomorphological evaluations reveal the mechanisms for accelerated bone repair through suppressed long-term inflammation,elevated collagen deposition,higher osteoblast activity,and enhanced angiogenesis.Together,our study highlights the clinical potential of the developed injectable Tetra-PEG hydrogel for treating anticoagulant-related post-extraction hemorrhage and improving socket healing.

止血黏合剂研究进展及设计考量

近年来,黏合剂在伤口闭合、止血和组织工程的应用中发展迅速,其不仅适用于湿组织的黏附,还可以适应组织器官的蠕动和机械拉伸,因而有防脱落性能,这对于动脉和器官出血来说尤为重要。随着技术的进一步发展,现有黏合剂可以通过不同策略对其改性,并且探索新材料,为黏合剂赋予了新的性能和用途,如药物递送、温敏性、光敏性等。尽管如此,对于未来黏合剂的设计及实际临床应用有许多值得商榷的地方。该文综述了传统黏合剂及其在止血应用中的最新研究进展,并讨论了未来黏合剂的设计和发展思路。

水凝胶生物粘合剂用于软组织止血修复的研究进展

及时的伤口干预处理对预防伤口感染、促进组织结构和功能恢复至关重要。目前临床手术中最常采用缝合线、钉合器进行伤口闭合处理。然而,这些传统的伤口缝合方式操作复杂繁琐且易对软组织造成二次损伤,尤其不适用于肝脏、脾脏等脆弱软组织以及急性主动脉破裂和无法控制的心脏大出血等问题。鉴于这些不足,水凝胶生物粘合剂作为缝合线和钉合器的理想替代品引起了人们的极大关注。本文概括总结了近些年来水凝胶生物粘合剂在伤口止血和组织愈合等方面的研究进展,并对水凝胶生物粘合剂未来的发展趋势进行了展望,其水下粘附性能和降解性能仍需迫切解决。

Smart bioadhesives for wound healing and closure

The high demand for rapid wound healing has spurred the development of multifunctional and smart bioadhesives with strong bioadhesion,antibacterial effect,real-time sensing,wireless communication,and on-demand treatment capabilities.Bioadhesives with bio-inspired structures and chemicals have shown unprecedented adhesion strengths,as well as tunable optical,electrical,and bio-dissolvable properties.Accelerated wound healing has been achieved via directly released antibacterial and growth factors,material or drug-induced host immune responses,and delivery of curative cells.Most recently,the integration of biosensing and treatment modules with wireless units in a closed-loop system yielded smart bioadhesives,allowing real-time sensing of the physiological conditions(e.g.,pH,temperature,uric acid,glucose,and cytokine)with iterative feedback for drastically enhanced,stage-specific wound healing by triggering drug delivery and treatment to avoid infection or prolonged inflammation.Despite rapid advances in the burgeoning field,challenges still exist in the design and fabrication of integrated systems,particularly for chronic wounds,presenting significant opportunities for the future development of next-generation smart materials and systems.

A“T.E.S.T.”hydrogel bioadhesive assisted by corneal cross-linking for in situ sutureless corneal repair

Corneal transplantation is an effective clinical treatment for corneal diseases,which,however,is limited by donor corneas.It is of great clinical value to develop bioadhesive corneal patches with functions of“Transparency”and“Epithelium&Stroma generation”,as well as“Suturelessness”and“Toughness”.To simultaneously meet the“T.E.S.T.”requirements,a light-curable hydrogel is designed based on methacryloylated gelatin(GelMA),Pluronic F127 diacrylate(F127DA)&Aldehyded Pluronic F127(AF127)co-assembled bi-functional micelles and collagen type I(COL I),combined with clinically applied corneal cross-linking(CXL)technology for repairing damaged cornea.The patch formed after 5 min of ultraviolet irradiation possesses transparent,highly tough,and strongly bio-adhesive performance.Multiple cross-linking makes the patch withstand deformation near 600%and exhibit a burst pressure larger than 400 mmHg,significantly higher than normal intraocular pressure(10-21 mmHg).Besides,the slower degradation than GelMA-F127DA&AF127 hydrogel without COL I makes hydrogel patch stable on stromal beds in vivo,supporting the regrowth of corneal epithelium and stroma.The hydrogel patch can replace deep corneal stromal defects and well bio-integrate into the corneal tissue in rabbit models within 4 weeks,showing great potential in surgeries for keratoconus and other corneal diseases by combining with CXL.

In situ Injectable Tetra-PEG Hydrogel Bioadhesive for Sutureless Repair of Gastrointestinal Perforation

Hydrogel bioadhesives represent promising and efficient alternatives to sutures or staples for gastrointestinal(GI)perforation management.However,several concerns remain for the existing bioadhesives including slow and/or weak adhesive,poor mechanical strength,low biocompatibility,and poor biodegradability,which largely limit their clinical application in GI perforation repair.In this work,we introduce an in situ injectable Tetra-PEG hydrogel bioadhesive(SS)composed of tetra-armed poly(ethylene glycol)amine(Tetra-PEG-NH2)and tetra-armed poly(ethylene glycol)succinimidyl succinate(Tetra-PEG-SS)for the sutureless repair of GI defects.The SS hydrogel exhibits rapid gelation behavior and high burst pressure and is capable of providing instant robust adhesion and fluid-tight sealing in the ex vivo porcine intestinal and gastric models.Importantly,the succinyl ester linkers in the SS hydrogel endow the bioadhesive with suitable in vivo degradability to match the new GI tissue formation.The in vivo evaluation in the rat GI injured model further demonstrates the successful sutureless sealing and repair of the intestine and stomach by the SS hydrogel with the advantages of neglectable postsurgical adhesion,suppressed inflammation,and enhanced angiogenesis.Together,our results support potential clinical applications of the SS bioadhesive for the high-efficient repair of GI perforation.

双功能基团抗生物附着提铀材料的制备及其吸附性能研究

研究了采用化学修饰将长链胺和偕胺肟功能基接枝到氯甲基化交联微球上,制备双功能基团抗生物附着提铀材料(LAAM),用于吸附海水中的铀,并对LAAM进行了红外表征和元素分析,考察了吸附时间、初始铀质量浓度、温度对LAAM对铀吸附性能的影响,绘制了吸附动力学曲线和吸附等温线,确定了解吸剂组成,分析了LAAM的抗生物附着性能。结果表明:适宜条件下,LAAM对海水中铀的吸附量为3.1 mg/g,具有良好的抗生物附着性能,有望用于海水提铀。

Adhesive cryogel particles for bridging confined and irregular tissue defects

Background Reconstruction of damaged tissues requires both surface hemostasis and tissue bridging.Tissues with damage resulting from physical trauma or surgical treatments may have arbitrary surface topographies,making tissue bridging challenging.Methods This study proposes a tissue adhesive in the form of adhesive cryogel particles(ACPs) made from chitosan,acrylic acid,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) and N-hydroxysuccinimide(NHS).The adhesion performance was examined by the 180-degree peel test to a collection of tissues including porcine heart,intestine,liver,muscle,and stomach.Cytotoxicity of ACPs was evaluated by cell proliferation of human normal liver cells(LO2)and human intestinal epithelial cells(Caco-2).The degree of inflammation and biodegradability were examined in dorsal subcutaneous rat models.The ability of ACPs to bridge irregular tissue defects was assessed using porcine heart,liver,and kidney as the ex vivo models.Furthermore,a model of repairing liver rupture in rats and an intestinal anastomosis in rabbits were established to verify the effectiveness,biocompatibility,and applicability in clinical surgery.Results ACPs are applicable to confined and irregular tissue defects,such as deep herringbone grooves in the parenchyma organs and annular sections in the cavernous organs.ACPs formed tough adhesion between tissues[(670.9±50.1) J/m^(2) for the heart,(607.6±30.0) J/m^(2) for the intestine,(473.7±37.0) J/m^(2) for the liver,(186.1±13.3) J/m^(2) for the muscle,and(579.3±32.3) J/m^(2) for the stomach].ACPs showed considerable cytocompatibility in vitro study,with a high level of cell viability for 3 d[(98.8±1.2)%for LO2 and(98.3±1.6)%for Caco-2].It has comparable inflammation repair in a ruptured rat liver(P=0.58 compared with suture closure),the same with intestinal anastomosis in rabbits(P=0.40 compared with suture anastomosis).Additionally,ACP-based intestinal anastomosis(less than 30 s) was remarkably faster than the conventional suturing process(more than 10 min).When ACPs degrade after surgery,the tissues heal across the adhesion interface.Conclusions ACPs are promising as the adhesive for clinical operations and battlefield rescue,with the capability to bridge irregular tissue defects rapidly.

Tuning gelatin-based hydrogel towards bioadhesive ocular tissue engineering applications

Gelatin based adhesives have been used in the last decades in different biomedical applications due to the excellent biocompatibility,easy processability,transparency,non-toxicity,and reasonable mechanical properties to mimic the extracellular matrix(ECM).Gelatin adhesives can be easily tuned to gain different viscoelastic and mechanical properties that facilitate its ocular application.We herein grafted glycidyl methacrylate on the gelatin backbone with a simple chemical modification of the precursor,utilizing epoxide ring-opening reactions and visible light-crosslinking.This chemical modification allows the obtaining of an elastic protein-based hydrogel(GELGYM)with excellent biomimetic properties,approaching those of the native tissue.GELGYM can be modulated to be stretched up to 4 times its initial length and withstand high tensile stresses up to 1.95 MPa with compressive strains as high as 80%compared to Gelatin-methacryloyl(GeIMA),the most studied derivative of gelatin used as a bioadhesive.GELGYM is also highly biocompatible and supports cellular adhesion,proliferation,and migration in both 2 and 3-dimensional cell-cultures.These characteristics along with its super adhesion to biological tissues such as cornea,aorta,heart,muscle,kidney,liver,and spleen suggest widespread applications of this hydrogel in many biomedical areas such as transplantation,tissue adhesive,wound dressing,bioprinting,and drug and cell delivery.

Effect of bioadhesive excipients on absorption of total flavonids from Puerariae Lobatae Radix transporting across Caco-2 cell monolayer

Objective: Pueraria total flavonids(PTF) can treat cardiovascular and cerebrovascular diseases, but it has poor membrane permeability and oral bioavailability. Some excipients, such as carbomer, chitosan, and hydroxypropyl methylcellulose, can improve the oral bioavailability. Traditional in vitro evaluation techniques, including the rat intestinal perfusion and cell line models, cannot evaluate PTF absorption and holistic transporters.Methods: This study evaluated excipients' adhesiveness and effect on PTF transport across Caco-2 cell monolayer. cDNA microarrays identified gene expression changes in Caco-2 cells exposed to PTF and PTF with excipients, and revealed the mechanism underlying the effect of excipients on PTF absorption.Results: In vitro adhesion and transport experiments across Caco-2 showed that excipients had higher adhesiveness to gastric mucosa and transport efficiency across Caco-2 cells than PTF alone. The interaction of PTF with excipients significantly changed the expression of some genes, which might influence the absorption rate of PTF.Conclusion: Different bioadhesive polymers can improve intestinal absorption of PTF, which was related to some genes affiliated to the ATP-binding cassette(ABC) and solute carrier transporter(SLC) to some extent.

Cohesion mechanisms for bioadhesives

Due to the nature of non-invasive wound closure,the ability to close different forms of leaks,and the potential to immobilize various devices,bioadhesives are altering clinical practices.As one of the vital factors,bioadhesives’strength is determined by adhesion and cohesion mechanisms.As well as being essential for adhesion strength,the cohesion mechanism also influences their bulk functions and the way the adhesives can be applied.Although there are many published reports on various adhesion mechanisms,cohesion mechanisms have rarely been addressed.In this review,we have summarized the most used cohesion mechanisms.Furthermore,the relationship of cohesion strategies and adhesion strategies has been discussed,including employing the same functional groups harnessed for adhesion,using combinational approaches,and exploiting different strategies for cohesion mechanism.By providing a comprehensive insight into cohesion strategies,the paper has been integrated to offer a roadmap to facilitate the commercialization of bioadhesives.

Engineering multifunctional bioadhesive powders through dynamic metal-ligand coordination

Bioadhesive gels with robust adhesion on wet and irregular tissue surfaces are desirable for clinical applications.Assembly of bioadhesive powders is an effective strategy for obtaining gels that adhere to wet and irregular tissue surfaces by absorbing interfacial water.However,current bioadhesive powders lack positive biological functions and are prone to postoperative adhesion.Here,we present a powder strategy based on metal-ligand coordination to create a series of bioadhesive polyacrylic acid(PAA)gels.In the gel network,metal ions(M^(n+))are used to coordinate with the carboxy ligands of PAA to form dynamic noncovalent crosslinks.The powders can absorb interfacial water and assemble into gels on wet and irregular tissue surfaces within a few seconds,forming an initial adhesion layer by electrostatic interactions.Furthermore,the polymers can diffuse into the tissue matrix,and metal-ligand coordination is reconstructed to enhance the adhesion.Moreover,with a cationic shield layer,the bioadhesive powders can effectively avoid postoperative adhesion.Importantly,M^(n+) ions endow the gel with customized biological functions.We demonstrate that the hemostatic,antibacterial,peroxidase-like catalytic,and photodetachment abilities of the gels by incorporating different M^(n+) ions.These advantages make the bioadhesive powder a promising platform for diverse tissue repair applications.