Improved hydration property of tissue adhesive/hemostatic microparticle based on hydrophobically-modified Alaska pollock gelatin.

The management of bleeding is an important aspect of endoscopic surgery to avoid excessive blood loss and minimize pain. In clinical settings, sprayable hemostatic particles are used for their easy delivery, adaptability to irregular shapes, and rapid hydration. However, conventional hemostatic particles present challenges associated with tissue adhesion. In a previous study, we reported tissue adhesive microparticles (C10-sa-MPs) derived from Alaska pollock gelatin modified with decyl groups (C10-sa-ApGltn) using secondary amines as linkages. The C10-sa-MPs adhere to soft tissues through a hydration mechanism. However, their application as a hemostatic agent was limited by their long hydration times, attributed to their high hydrophobicity. In this study, we present a new type microparticle, C10-am-MPs, synthesized by incorporating decanoyl group modifications into ApGltn (C10-am-ApGltn), using amide bonds as linkages. C10-am-MPs exhibited enhanced hydration characteristics compared to C10-sa-MPs, attributed to superior water absorption facilitated by amide bonds rather than secondary amines. Furthermore, C10-am-MPs demonstrated comparable tissue adhesion properties and underwater adhesion stability to C10-sa-MPs. Notably, C10-am-MPs exhibited accelerated blood coagulation in vitro compared to C10-sa-MPs. The application of C10-am-MPs in an in vivo rat liver hemorrhage model resulted in a hemostatic effect comparable to a commercially available hemostatic particle. These findings highlight the potential utility of C10-am-MPs as an effective hemostatic agent for endoscopic procedures and surgical interventions.

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.

Injectable microcapillary network hydrogels engineered by liquid-liquid phase separation for stem cell transplantation.

Injectable hydrogels are promising carriers for cell delivery in regenerative medicine. However, injectable hydrogels composed of crosslinked polymer networks are often non-microporous and prevent biological communication with host tissues through signals, nutrients, oxygen, and cells, thereby limiting graft survival and tissue integration. Here we report injectable hydrogels with liquid-liquid phase separation-induced microcapillary networks (µCN) as stem cell-delivering scaffolds. The molecular modification of gelatin with hydrogen bonding moieties induced liquid-liquid phase separation when mixed with unmodified gelatin to form µCN structures in the hydrogels. Through spatiotemporally controlled covalent crosslinking and dissolution processes, porous µCN structures were formed in the hydrogels, which can enhance mass transport and cellular activity. The encapsulation of cells with injectable µCN hydrogels improved cellular spreading, migration, and proliferation. Transplantation of mesenchymal stem cells with injectable µCN hydrogels enhanced graft survival and recovered hindlimb ischemia by enhancing material-tissue communication with biological signals and cells through µCN. This facile approach may serve as an advanced scaffold for improving stem cell transplantation therapies in regenerative medicine.

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.

Improved Swelling Property of Tissue Adhesive Hydrogels Based on α-Cyclodextrin/Decyl Group-Modified Alaska Pollock Gelatin Inclusion Complexes.

Adhesives/sealants are used after suturing to prevent leakage of cerebrospinal fluid from an anastomotic site. Commercial adhesives/sealants have been used to close the cerebral dura. However, swelling of the cured adhesives/sealants induces increased intracranial pressure and decreases the strength of the seal. In the present study, tissue adhesive hydrogels with improved swelling property using inclusion complex composed of α-cyclodextrin (αCD) and decyl group (C10)-modified Alaska pollock-derived gelatin (C10-ApGltn) with a high degree of substitution (DS) (>20 mol%) are developed. Viscosity of C10-ApGltn with a high DS solution remarkably decreased by the addition of αCD. The resulting αCD/C10-ApGltn adhesive hydrogel composed of αCD/C10-ApGltn inclusion complexes and poly(ethylene glycol) (PEG)-based crosslinker showed improved swelling property after immersion in saline. Also, the resulting adhesive has a significantly higher burst strength than fibrin-based adhesives and is as strong as a PEG-based adhesive. Quantitative analysis of αCD revealed that the improved swelling property of the resulting adhesive hydrogels is induced by the release of αCD from cured adhesive, and the subsequent assembly of decyl groups in the saline. These results suggest that adhesives developed using the αCD/C10-ApGltn inclusion complex can be useful for closing the cerebral dura mater.

Tissue-Adhesive Decellularized Extracellular Matrix Patches Reinforced by a Supramolecular Gelator to Repair Abdominal Wall Defects.

Implantation of surgical meshes composed of synthetic and biological materials has been applied for abdominal wall defect repair. Despite many efforts, there are no reliable meshes that fully satisfy clinical requirements because of their lack of biodegradability, mechanical strength, and tissue-adhesive properties. Here, we report biodegradable, decellularized extracellular matrix (dECM)-based biological patches to treat abdominal wall defects. By incorporating a water-insoluble supramolecular gelator that forms physical cross-linking networks through intermolecular hydrogen bonding, dECM patches were reinforced to improve mechanical strength. Reinforced dECM patches possessed higher tissue adhesion strength and underwater stability compared with the original dECM because of enhanced interfacial adhesion strength. In vivo experiments using an abdominal wall defect rat model showed that reinforced dECM patches induced collagen deposition and the formation of blood vessels during material degradation, and the accumulation of CD68-positive macrophages was suppressed compared to nonbiodegradable synthetic meshes. Tissue-adhesive and biodegradable dECM patches with improved mechanical strength by a supramolecular gelator have enormous potential for use in the repair of abdominal wall defects.

Effect of particle size on the tissue adhesion and particle floatation of a colloidal wound dressing for endoscopic treatments.

Endoscopic submucosal dissection (ESD) is a minimally invasive technique that is widely used to remove gastrointestinal tumors. However, because the walls of the duodenum and large intestine are thin, perforation can easily occur after ESD. We have previously reported that alkyl group-modified Alaska pollock gelatin-based microparticles (C10Ps) formed a colloidal gel that could adhere to defects and close perforations, driven by hydrophobic interactions. The present study focused on the effect of particle size on the colloidal gel properties and the floatation of C10Ps in the air in the delivery of C10Ps. We prepared C10Ps with different particle sizes from 0.1 to 100 µm. The storage modulus and adhesion strength of the C10P colloidal gel increased with decreasing particle size. All the C10Ps formed a colloidal gel layer on duodenum tissue after being sprayed from an endoscopic device. The underwater stability and burst strength of C10Ps with a particle size of 0.1 and 1 µm were higher than for larger C10Ps. Floating of the small-sized C10Ps in the air was observed. The results indicated that C10Ps with a size of 1 µm had suitable properties for use in endoscopic treatments. STATEMENT OF SIGNIFICANCE: We previously reported tissue adhesive microparticles as a spray-deliverable wound dressing in gastrointestinal tissues. However, their functions depending on particle size have not yet been clarified. In the present study, we prepared decyl group-modified Alaska pollock gelatin nano and microparticles (C10Ps) with different particle sizes from 0.1 to 100 µm and evaluated the effect of particle size on the colloidal gel properties (rheological property, underwater stability and perforation-closing ability) and the floatation of C10Ps in the air in the delivery of C10Ps.

Enhanced burst strength of catechol groups-modified Alaska pollock-derived gelatin-based surgical adhesive.

Aortic anastomotic leak is a potentially fatal complication that can occur after treatment of aortic dissection or aneurysm. Several surgical adhesives have been used to prevent this complication, but all have problems with regard to tissue adhesion or biocompatibility. In the present study, we developed a surgical adhesive composed of boric acid-protected catechol groups-modified Alaska pollock-derived gelatin (Cat-ApGltn) and a poly(ethylene glycol)-based crosslinker (4S-PEG). By avoiding oxidation of catechol groups using boric acid, resulting Cat-ApGltn adhesive formed a strong hydrogel by double crosslinking: chemical crosslinking by 4S-PEG, and chemical and physical crosslinking by the catechol groups. The catechol groups modification contributed to increased bulk strength and decreased gelation time/swelling ratios. The Cat-ApGltn adhesive, in which 7.8 mol% of the amino groups of the original ApGltn (Org-ApGltn) were modified with catechol groups, demonstrated 2.3 times higher burst strength compared with the Org-ApGltn adhesive, and 3.9 times higher burst strength compared with a commercial fibrin adhesive. When the Cat-ApGltn adhesive was implanted subcutaneously into rats, it induced only weak inflammation similar to that induced by the Org-ApGltn adhesive, and was completely degraded within 2 months. Therefore, the Cat-ApGltn adhesive has great potential for use in the field of cardiovascular surgery.

Liquid-Liquid Phase-Separated Hydrogel with Tunable Sol-Gel Transition Behavior as a Hotmelt-Adhesive Postoperative Barrier.

Postoperative barriers have been widely used to prevent adhesions. However, there are currently few barriers that satisfy clinical requirements, such as tissue adhesion, operability, and biocompatibility. Inspired by the adhesion system of living organisms, we report a liquid-liquid phase-separated hydrogel as a single-syringe hotmelt-type postoperative barrier. Mixing polyethylene glycol with gelatin formed liquid-liquid phase-separated hydrogels through segregative liquid-liquid phase separation. Incorporation of a liquid-liquid phase-separated system into gelatin can enhance the sol-gel transition temperature to give a hotmelt-adhesive property to hydrogels. Hotmelt-adhesive hydrogels became a sol phase and cohered into tissue gaps when warmed and solidified at body temperature to adhere to soft tissues. The hydrogels exhibited tissue adhesion to large intestine tissues and showed improved mechanical strength, gelation time, and shear-thinning properties. In rat cecum-abdominal adhesion models, it was confirmed that the resulting hydrogels prevented abdominal adhesion and did not prevent tissue regeneration. Hotmelt-adhesive hydrogels with high tissue adhesive properties, operability, and biocompatibility have enormous potential as barriers to prevent postoperative complications.

Vaginal Sparing Radiotherapy Using IMPT and Daily Dilator Placement for Women with Anal Cancer.

Sexual dysfunction is a common toxicity and detrimental for the quality of life of women treated with chemoradiotherapy for anal cancer. Sexual dysfunction occurs because the vagina is closely approximated to the anal canal and typically receives substantial doses of radiation. Strategies for mitigation have largely been focused on posttreatment therapy and symptom management. The use of daily vaginal dilator placement during radiotherapy to mitigate dose to the vagina has been previously explored with modest gains, while proton therapy is under active investigation for the treatment of anal cancer. Use of proton therapy for anal cancer reduces dose to some organs at risk but may inadvertently increase vaginal toxicity if the proton beam terminates in the vaginal tissue. Herein, we present the case histories of 2 women treated for squamous cell carcinoma of the anal canal with the novel combination of intensity-modulated proton therapy and daily vaginal dilator placement to maximally reduce dose to the vagina and protect it from areas of increased energy deposition at the end of the proton range.

Prevention of postoperative adhesion with a colloidal gel based on decyl group-modified Alaska pollock gelatin microparticles.

Postoperative adhesion, bonding of the abdominal wall to damaged organs, causes severe complications after abdominal surgery. Despite the availability of physical barriers (i.e., solutions, films, and hydrogels), adhesion prevention materials that are a single-substance system with stability in wet tissue and ease of use have not been reported. Here, we report a microparticle based, sprayable adhesion prevention material comprising decyl group modified Alaska pollock gelatin (C10-ApGltn). C10-ApGltn microparticles (C10-MPs) were prepared by a coacervation method, freeze drying, and thermal crosslinking. The C10-MPs adhered to and formed a colloidal gel layer on intestinal serosal tissue by hydration without any crosslinking agents. After hydration of the C10-MPs, the resulting colloidal gel layer did not adhere to other tissues. Additionally, the C10-MP colloidal gel layer formed on the stomach serosal tissue showed stability when submersed in saline for 2 days. The colloidal gel layer also showed tissue followability. An in vivo rat adhesion model revealed that C10-MP colloidal gel layer on the cecum and abdominal wall defects effectively reduced postoperative adhesion and induced tissue remodeling, including re-mesothelialization. Therefore, C10-MPs are a potential anti-adhesion material for preventing postoperative adhesion. STATEMENT OF SIGNIFICANCE: We evaluated the postoperative adhesion prevention ability of a colloidal gel based on decyl group modified Alaska pollock gelatin (ApGltn) microparticles (C10-MPs). These microparticles are sprayable and form a colloidal gel with only hydration on the gastrointestinal tissue. We revealed that the modification of the decyl group into ApGltn improved the stability of C10-MP colloidal gel on the tissue by hydrophobic interaction in the in-vitro experiments. The gel prevented postoperative adhesion by being a physical barrier in the in-vivo rat adhesion model.

Hotmelt tissue adhesive with supramolecularly-controlled sol-gel transition for preventing postoperative abdominal adhesion.

Postoperative adhesion is a serious and frequent complication, but there is currently no reliable anti-adhesive barrier available due to low tissue adhesiveness, undesirable chemical reactions, and poor operability. To overcome these problems, we report a single-syringe hotmelt tissue adhesive that dissolves upon warming over 40 °C and coheres at 37 °C as a postoperative barrier. Tendon-derived gelatin was conjugated with the ureidopyrimidinone unit to supramolecularly control the sol-gel transition behavior. This functionalization improved bulk mechanical strength, tissue-adhesive properties, and stability under physiological conditions through the augmentation of intermolecular hydrogen bonding by ureidopyrimidinone unit. This biocompatible adhesive prevented postoperative adhesion between cecum and abdominal wall in adhesion models of rats. This hotmelt tissue adhesive has enormous potential to prevent postoperative complications and may contribute to minimally invasive surgery. STATEMENT OF SIGNIFICANCE: There is a strong need to develop medical tissue adhesives with high biocompatibility, tissue adhesiveness, and operatability to prevent postoperative complications. In this report, single syringe, hotmelt-type tissue adhesive was developed by controlling sol-gel transition behavior of gelatin through supramolecular approach. The functionalization of gelatin with quadruple hydrogen bonding improved key features necessary for anti-adhesive barrier including bulk mechanical strength, tissue adhesive property, stability under physiological conditions, and anti-adhesive property. The hotmelt tissue adhesive can be used for a sealant, hemostatic reagent, and wound dressing to prevent postoperative complications including delayed bleeding, perforation, and inflammation and contribute to minimally invasive surgery.

A Dosimetric Comparison of Lattice, Brass, and Proton Grid Therapy Treatment Plans.

PURPOSE: Our purpose was to dosimetrically compare volumetric modulated arc therapy (VMAT) lattice radiation therapy (LRT), brass, and proton grid therapy planning techniques and suggest potential clinical applications for each. METHODS AND MATERIALS: Four plans delivering 20 Gy in 1 fraction were created for each of 22 patients. Brass and proton grid plans used a single static field and the same beam angle. Proton grid plans used the same beam size and spacing as the brass block. Two VMAT LRT plans were generated for each patient: one with 1-cm diameter lattice points spaced 2-cm center-to-center (2-cm VMAT) and another with 1.5-cm diameter lattice points spaced 3-cm center-to-center (3- cm VMAT). Maximum, minimum, mean, and equivalent uniform dose and the dose to 90%, 50%, 20%, 10%, and 5% (D90%[%], D50%[%], etc) of gross tumor volume (GTV) were reported. D10%/D90% characterized dose heterogeneity. Normal tissue dose was generalized by the maximum dose and volume in cubic centimeters of tissue outside the GTV receiving 30% and 50% of prescription (body-GTV V30%[cm3]; body-GTV V50%[cm3]). RESULTS: VMAT LRT plans delivered the highest maximum GTV doses while brass and proton plans delivered higher D5%(%), D10%(%), and D20%(%) values. D50%(%), D90%(%), and minimum dose varied little between plan types. Proton and brass plans had the highest dose heterogeneity. Two-centimeter VMAT and brass grid plans had the highest mean GTV doses. Two-centimeter VMAT plans had the highest equivalent uniform dose, followed by 3-cm VMAT, brass, and proton plans. VMAT LRT plans exhibited the lowest normal tissue maximum and body GTV V30%(cm3) and body GTV V50%(cm3) values. CONCLUSIONS: An in-depth comparison of target and normal tissue dosimetric parameters for common photon and proton grid therapy planning techniques was made. Strengths of each plan type were noted leading to general recommendations on usage.

Robust closure of post-endoscopic submucosal dissection perforation by microparticle-based wound dressing.

Endoscopic submucosal dissection (ESD) has been used as a minimally invasive cancer treatment for early-stage gastrointestinal cancer. However, cancer dissection in thin tissues, such as the duodenum and large intestine, often cause post-ESD and delayed perforation, which elicit severe complications. In this study, we report a microparticle-based wound dressing with hydrophobically-modified gelatin that can close the perforation after ESD. Hydrophobized microparticles were prepared using a coacervation method in a water/ethanol mixed solvent. The optimized alkyl chain length and degree of substitution of hydrophobic groups improved the mechanical strength of the hydrogel formed by hydration and fusion of the microparticles. The hydrogels formed on tissue defects revealed higher burst strength in ex vitro perforation models using duodenum, large intestine, and stomach under wet conditions compared with hydrogels without hydrophobic modification. The particle fusion was determined to be a crucial step to yield a high burst strength. An in vivo degradability evaluation showed that microparticle hydrogels subcutaneously implanted in rats degraded within 14 days. The microparticle wound dressing is expected to be applicable to post-ESD perforation and prevent delayed perforation.

Clinical Implementation of Preoperative Short-Course Pencil Beam Scanning Proton Therapy for Patients With Rectal Cancer.

PURPOSE: For treatment of rectal cancer, pencil beam scanning proton therapy (PBS-PT) may reduce radiation exposure to normal tissues compared with 3-dimensional conformal photon radiation therapy (3DCRT) or volumetric modulated arc photon radiation therapy (VMAT). The purpose of this study was to report the clinical implementation and dosimetric analysis of preoperative short-course PBS-PT for rectal cancer. METHODS AND MATERIALS: Eleven patients with stage IIA-IVB rectal cancer received preoperative short-course (25 Gy in 5 fx) PBS-PT between 2018 and 2019 preceding curative-intent total mesorectal excision. PBS-PT plans were generated using single-field optimization with 2 posterior-oblique fields. Verification computed tomography scans were performed on the first 3 days of treatment. Each patient had a backup 3DCRT and VMAT plan. RESULTS: Clinical target volume coverage was similar between PBS-PT, 3DCRT, and VMAT. PBS-PT had statistically significant reductions in dose to the small bowel, large bowel, bladder, and femoral heads across multiple dosimetric parameters. All patients completed PBS-PT as planned without need for replanning. All computed tomography verification scans demonstrated good target coverage with clinical target volume V100 > 95%. CONCLUSIONS: Preoperative short-course PBS-PT has been successfully implemented and offers a significant reduction of dose to normal tissues. Prospective studies are warranted to evaluate if dosimetric advantages translate into clinical benefit.

Verification of calculated skin doses in postmastectomy helical tomotherapy.

PURPOSE: To verify the accuracy of calculated skin doses in helical tomotherapy for postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: In vivo thermoluminescent dosimeters (TLDs) were used to measure the skin dose at multiple points in each of 14 patients throughout the course of treatment on a TomoTherapy Hi·Art II system, for a total of 420 TLD measurements. Five patients were evaluated near the location of the mastectomy scar, whereas 9 patients were evaluated throughout the treatment volume. The measured dose at each location was compared with calculations from the treatment planning system. RESULTS: The mean difference and standard error of the mean difference between measurement and calculation for the scar measurements was -1.8% ± 0.2% (standard deviation [SD], 4.3%; range, -11.1% to 10.6%). The mean difference and standard error of the mean difference between measurement and calculation for measurements throughout the treatment volume was -3.0% ± 0.4% (SD, 4.7%; range, -18.4% to 12.6%). The mean difference and standard error of the mean difference between measurement and calculation for all measurements was -2.1% ± 0.2% (standard deviation, 4.5%: range, -18.4% to 12.6%). The mean difference between measured and calculated TLD doses was statistically significant at two standard deviations of the mean, but was not clinically significant (i.e., was <5%). However, 23% of the measured TLD doses differed from the calculated TLD doses by more than 5%. CONCLUSIONS: The mean of the measured TLD doses agreed with TomoTherapy calculated TLD doses within our clinical criterion of 5%.