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Osteoarthritis (OA) is characterized by symptoms such as abnormal lubrication function of synovial fluid and heightened friction on the cartilage surface in its early stages, prior to evident cartilage damage. Current early intervention strategies employing lubricated hydrogels to shield cartilage from friction often overlook the significance of hydrogel-cartilage adhesion and enhancement of the cartilage extracellular matrix (ECM). Herein, we constructed a hydrogel based on dihydrazide-modified hyaluronic acid (HA) (AHA) and catechol-conjugated aldehyde-modified HA (CHA), which not only adheres to the cartilage surface as an effective lubricant but also improves the extracellular environment of chondrocytes in OA. Material characterization experiments on AHA/CHA hydrogels with varying concentrations validated their exceptional self-healing capabilities, superior injectability and viscoelasticity, sustained adhesion strength to cartilage, and a low friction coefficient. Chondrocytes exhibited robust adhesion and proliferation on the AHA/CHA hydrogel surface, with the upregulation of cartilage matrix protein expression. Intra-articular injection of AHA/CHA hydrogels was performed following destabilization of the medial meniscus (DMM) surgery in mice to assess its protective effect on cartilage. The AHA/CHA hydrogel effectively attenuated the degree of cartilage wear, facilitated chondrocytes' anabolic metabolism, and restored the ECM of cartilage. Therefore, the AHA/CHA hydrogel emerges as a promising therapeutic approach in clinical practices of OA treatment.

This preclinical proof-of-concept study aimed to evaluate the effectiveness of secretome therapy in diabetic mice with pressure ulcers. We utilized a custom-made hyaluronic acid (HA)-based porous sponge, which was rehydrated either with normal culture medium or secretome derived from human mesenchymal stromal cells (MSCs) to achieve a hydrogel consistency. Following application onto skin ulcers, both the hydrogel-only and the hydrogel + secretome combination accelerated wound closure compared to the vehicle group. Notably, the presence of secretome significantly enhanced the healing effect of the hydrogel, as evidenced by a thicker epidermis and increased revascularization of the healed area compared to the vehicle group. Notably, molecular analysis of healed skin revealed significant downregulation of genes involved in delayed wound healing and abnormal inflammatory response in ulcers treated with the hydrogel + secretome combination, compared to those treated with the hydrogel only. Additionally, we found no significant differences in therapeutic outcomes when comparing the use of secretome from fetal dermal MSCs to that from umbilical cord MSCs. This observation is supported by the proteomic profile of the two secretomes, which suggests a shared molecular signature responsible of the observed therapeutic effects.

The management of chronic wounds in diabetes remains challenging due to the complexity of impaired wound healing, delayed healing, susceptibility to infection, and elevated risk of reopening, highlighting the need for effective chronic wound management with innovative approaches such as multifunctional hydrogels. Here, we have produced HA-DA@rhCol hydrogels consisting of dopamine-modified hyaluronic acid and recombinant human collagen type-III (rhCol) by oxidative coupling of the catechol group using the H2O2/HRP catalytic system. The post-reactive hydrogel has a good porous structure, swelling rate, reasonable degradation, rheological and mechanical properties, and the catechol group and dopamine impart to the hydrogel tissue adhesiveness, antioxidant capacity, and excellent photothermal effects leading to superior in vitro antimicrobial activity. In addition, the ability of rhCol to confer hydrogels to promote angiogenesis and wound repair has also been investigated. Cytotoxicity and hemolysis tests demonstrated the good biocompatibility of the hydrogel. Wound closure, collagen deposition and immunohistochemical examination confirmed the ability of the hydrogel to promote diabetic wound healing. In summary, the adhesive hemostatic antioxidative hydrogel with rhCol to promote wound healing in diabetic rat is an excellent chronic wound dressing.

Hyaluronic acid (HA)-based biopolymer hydrogels are promising therapeutic dressings for various wounds but still underperform in treating diabetic wounds. These wounds are extremely difficult to heal and undergo a prolonged and severe inflammatory process due to bacterial infection, overexpression of reactive oxygen species (ROS), and insufficient synthesis of NO. In this study, a dynamic crosslinked hyaluronic acid (HA) hydrogel dressing (Gel-HAB) loaded with allomelanin (AMNP)-N, N′-dis-sec-butyl-N, N′-dinitroso-1, 4-phenylenediamine (BNN6) nanoparticles (AMNP-BNN6) was developed for healing diabetic wounds. The dynamic acylhydrazone bond formed between hydrazide-modified HA (HA-ADH) and oxidized HA (OHA) makes the hydrogel injectable, self-healing, and biocompatible. The hydrogel, loaded with AMNP-BNN6 nanoparticles, exhibits promising ROS scavenging ability and on-demand release of nitric oxide (NO) under near-infrared (NIR) laser irradiation to achieve mild photothermal antibacterial therapy (PTAT) (∼ 48 °C). Notably, the Gel-HAB hydrogel effectively reduced the oxidative stress level, controlled infections, accelerated vascular regeneration, and promoted angiogenesis, thereby achieving rapid healing of diabetic wounds. The injectable self-healing nanocomposite hydrogel could serve as a mild photothermal-enhanced antibacterial, antioxidant, and nitric oxide release platform for the treatment of diabetic wounds. [Display omitted] • A hyaluronic acid hydrogel with excellent synergistic antimicrobial properties via mild photothermal effect and NO release. • Hydrogel effectively reduces the inflammatory microenvironment and promotes the growth of M2 macrophages. • Hydrogel effectively manages diabetic wound infections, reduces inflammation levels, promotes angiogenesis and collagen deposition, and accelerates rapid wound healing. [ABSTRACT FROM AUTHOR]

Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica. [Display omitted] [ABSTRACT FROM AUTHOR]

Photoaging, primarily caused by ultraviolet (UV) light, is the major factor in extrinsic skin aging. Existing anti-photoaging strategies mainly focus on early sun protection or repairing damaged skin, lacking a comprehensive treatment strategy. Therefore, this study developed a dressing that actively shields against UV radiation and repairs photoaged skin, offering double protection. This study utilized exosome-like nanovesicles derived from Olea europaea leaves (OLELNVs), enhancing them into a potent core biomaterial with high-dose effects and skin-friendly, non-cytotoxic inhibition of cell aging. These nanovesicles were incorporated into a cross-linked hyaluronic acid (HA) and tannic acid (TA) hydrogel with strong UV-absorbing properties, creating the OLELNVs@HA/TA hydrogel system. In vitro and in vivo experiments demonstrated that OLELNVs@HA/TA hydrogel can effectively reduce UV-induced skin damage and promote skin repair and regeneration. Additionally, RNA-seq and clustering analysis of miR168a-5p predicted targets revealed significant down-regulation of the NF-κB signaling pathway, mediating inflammatory aging responses. Overall, the OLELNVs@HA/TA hydrogel represents a novel dual-strategy approach for clinical application in combating photoaging.

Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH2) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment.

Despite the high complete response rate of fertility-sparing treatment in early-stage endometrial cancer (EC), the low pregnancy rate is a clinical challenge. Whether endometrium-derived mesenchymal stem cells (eMSCs) can repair damaged endometrium after EC reversal remains unclear. This study explored the potential therapeutic effects of eMSCs with suitable scaffold materials on endometrial damage caused by EC. Here, appropriate engineering scaffold materials were compared to identify the most suitable materials to carry eMSCs. Then, safety and efficacy evaluations of eMSCs with a suitable hyaluronic acid hydrogel (eMSCs/HA-GEL) were investigated in in vivo experiments with subcutaneous xenotransplantation in Balb/C nude mice and a model of endometrial mechanical injury in rats. HA-GEL has minimal cytotoxicity to eMSCs compared to other materials. Then, in vitro experiments demonstrate that eMSCs/HA-GEL enhance the inhibitory effects of progestins on EC cell biological behaviors. eMSCs/HA-GEL significantly inhibit EC cell growth and have no potential safety hazards of spontaneous tumorigenesis in Balb/C nude mouse subcutaneous xenotransplantation assays. eMSCs/HA-GEL intrauterine transplantation effectively increases endometrial thickness and glandular number, improves endometrial blood supply, reduces fibrotic areas, and improves pregnancy rates in a rat endometrial mechanical injury model. GFP-eMSCs/HA-GEL intrauterine transplantation in rats shows more GFP-eMSCs in the endometrium than GFP-eMSCs transplantation alone, and no tumor formation or suspicious cell nodules are found in the liver, kidney, or lung tissues. Our results reveal the safety and efficacy of eMSCs/HA-GEL in animal models and provide preliminary evidence for the use of eMSCs/HA-GEL as a treatment for EC-related endometrial damage. [ABSTRACT FROM AUTHOR]

Hao Zhang,1,* Ping Zhou,1,* Yi Jiang,1 Liu Li,1 Fei Ju,2 Quan Cheng,1 You Lang Zhou,2 Yuan Zhou1 1Department of Pain, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, People’s Republic of China; 2Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan Zhou; You Lang Zhou, Tel +86 0513 85052222 ; +86 0513 85052488, Email nina_shine@126.com; zhouyoulang@ntu.edu.cnIntroduction: Esketamine, one of the few non-opioid potent analgesics, has demonstrated efficacy in the treatment of various chronic pain, particularly neuropathic pain. However, its potential clinical applications are confined due to its short half-life and severe side effects including delirium, hallucinations, and other psychiatric symptoms. Here, we reported a nanosized drug delivery system for sustained-release esketamine based on polylactic-co-glycolic acid (PLGA) nanoparticles and hyaluronic acid (HA) hydrogel.Results: In this study, esketamine in the delivery system was continuously released in vitro for at least 21 days, and spinal nerve root administration of the delivery system successfully attenuated (spinal nerve ligation) SNL-induced pain hypersensitivity for at least 14 days. Notably, the excitability of neurons in murine dorsal root ganglion (DRG) was inhibited and the activation of astrocytes in the spinal cord was additionally reduced after administration. Finally, there was no obvious pathophysiological change in the nerves at the administration site after treatment at 14 days.Conclusion: These results indicate that the sustained-release esketamine based on the nanoparticle-hydrogel delivery system can safely produce a lasting analgesic effect on SNL mice, and its mechanism might be related to modulating the activation of astrocytes in the spinal cord and inhibiting the excitability of neurons in DRG.Keywords: esketamine, nanoparticles, hyaluronic acid hydrogel, neuropathic pain

Hyaluronic acid (HA) hydrogels have shown promise as biomaterials for soft tissue engineering applications due to their biocompatibility and ability to mimic the extracellular matrix (ECM). However, their limited cell adhesion properties and the need for improved crosslinking methods have hindered their widespread use. In this study, we developed an ECM-mimicking HA hydrogel reinforced with alkaline hydrolyzed (1 M NaOH) fragmented (1.5 cm×1.5 cm) electrospun polycaprolactone (PCL) fibers to enhance cell adhesion and mechanical properties of HA hydrogel. Formation of HA hydrogel was achieved through a thiol-ene click reaction, which is initiated by exposure to visible blue light-activated biocompatible photoinitiator, riboflavin phosphate. The incorporation of alkaline hydrolyzed PCL fiber fragments (PFF) (0 %, 0.1 %, and 1 % w/v) into HA hydrogel precursor solution significantly increased the mechanical stiffness of the HA hydrogel, with the storage modulus ranging from 18.6 ± 0.7 Pa to 216.0 ± 38.2 Pa. The cytocompatibility of the PCL fiber-reinforced HA hydrogel was evaluated using NIH/3T3 fibroblasts. The results demonstrated improved cell adhesion, proliferation, and enhanced cellular functions, including increased production of glycosaminoglycans (GAGs) and collagen, in the PCL fiber-reinforced HA hydrogel compared to the control HA hydrogel. These findings suggest that the developed PCL fiber-reinforced HA hydrogel system, with tunable mechanical properties and excellent cytocompatibility, has potential applications in soft tissue engineering and regenerative medicine. [Display omitted] • NaOH-treated PCL fibers incorporated into HA hydrogel scaffold. • PCL fiber increased HA hydrogel storage modulus 11.6-fold. • PCL-HA hydrogel showed excellent cytocompatibility with fibroblasts. • Fibroblasts exhibited improved adhesion and proliferation. • Potential applications in soft tissue engineering. [ABSTRACT FROM AUTHOR]

Due to its role as a free radical signal-transducing agent with a short lifespan, precise measurement of nitric oxide (●NO) levels presents significant challenges. Various analytical techniques offer distinct advantages and disadvantages for ●NO detection. This research aims to simplify the detection process by developing a hydrogel system using iron(III)-protoporphyrin IX (hemin)-loaded hyaluronan for the detection of ●NO in solution. Various hydrogel formulations were created, and the effects of their components on hydrogel-supported luminol chemiluminescence (CL) kinetics, radical scavenging, and physicochemical properties were analysed through factorial analysis. The candidate formulations were then evaluated using two ●NO donors. An increase in the degree of crosslinking in unloaded formulations enhanced interactions with the CL reaction components, hydrogen peroxide (H 2 O 2) and luminol, thereby affecting light generation. However, hemin loading negated these effects, resulting in more prominent luminescence kinetics in formulations with lower crosslinking degrees. Similarly, ●NO influenced the kinetics differently, interacting with both the CL reaction and hydrogel components. Hemin-loaded formulations exhibited enhanced signal propagation when exposed to ●NO, followed by H 2 O 2 and luminol, whereas reversing the order of addition inhibited this propagation. The magnitude of these luminescence changes depended on the type and concentration of the ●NO donor, demonstrating greater sensitivity to ●NO levels compared to amperometric sensing. These findings suggest that the studied hydrogel platform has potential for the facile and accurate detection of ●NO in solution, requiring minimal sample sizes. [Display omitted] • Different hemin-loaded hyaluronic acid hydrogel formulations were fabricated. • The influence of formulation on the luminescence generation was studied. • This assessment was performed in the absence/presence of two nitric oxide donors. • The crosslinking degree controlled the distribution of hemin molecules in hydrogel. • This distribution controlled reactivity towards nitric oxide and light generated. [ABSTRACT FROM AUTHOR]

Diabetic patients often struggle with wound healing and are at higher risk of infections, necessitating the development of a stretchable, adhesive hydrogel dressing with antibacterial and angiogenesis-promoting properties. In this study, we synthesized a series of adhesive, antibacterial and anti-inflammatory hydrogels using free radical polymerization with materials including methacrylated hyaluronic acid (HAMA), N-[tris(hydroxymethyl)methyl]acrylamide (THMA), and 3-(bis(pyridin-2-ylmethyl)amino)propyl methacrylate (DPAMA). By leveraging the strong affinity of zinc(II)-dipicolylamine coordination complexes for the phosphorylated groups in dexamethasone sodium phosphate (DMSP), Zn 2+ and DMSP were successfully incorporated into the hydrogel. The results demonstrated that the hydrogels possessed excellent adhesiveness and mechanical properties, enabling them to adhere closely to the skin while remaining easily removable without causing trauma. Antibacterial tests demonstrated significant inhibitory effects against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), attributed to the slow release of Zn 2+ , which effectively suppressed bacterial growth. Additionally, the slow release of DMSP provided strong anti-inflammatory effects. The DHTDZ2 hydrogel, containing 1.5 mg/mL Zn 2+ and 4 mg/mL DMSP, significantly accelerated the healing of full-thickness skin wounds. In vitro angiogenesis, immunofluorescence, and immuno-histochemical results further confirmed that the DHTDZ2 hydrogel promoted angiogenesis and reduced the expression of pro-inflammatory factors. In summary, the hydrogel is an effective wound healing dressing that can reduce wound infections and inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cell-surface engineering holds great promise in boosting endogenous stem cell attraction for tissue regeneration. However, challenges such as cellular internalization of ligand and the dynamic nature of cell membranes often complicate ligand-receptor interactions. The aim of this study is to harness the innovative potential of programmable tetrahedral framework nucleic acid (tFNA) to enable precise, tunable ligand-receptor interactions, thereby improving stem cell recruitment efficiency. This approach involves experimental screening and theoretical analysis using dissipative particle dynamics. The results demonstrate that altering the flexibility and topology of ligands on tFNA changes their cellular internalization and membrane binding efficiency. Furthermore, optimizing the distribution of the mesenchymal stem cell (MSC)-binding aptamer 19S (Apt19S) on the tFNA enhances the stem cell capture efficiency. Following successful in vitro MSC capture, Apt19S-modified tFNA is chemically linked to a hyaluronic acid hydrogel, forming an efficient "stem cell catcher" system. Subsequent in vivo experiments demonstrate that this system effectively promotes early stem cell recruitment and accelerates bone regeneration in different bone healing scenarios, including cranial and maxillary defects., (© 2024 Wiley‐VCH GmbH.)

Introduction: Ischemia followed by apoptosis and follicles mortality are problems that occur after cryopreservation and ovarian tissue transplantation. The present study used hyaluronic acid hydrogel as a capsule to reduce ischemia and apoptosis in vitrified ovarian tissue transplantation of rats. Material & Methods: In total, 22 adult female rats (~ 8-week old) with normal estrous cycle were ovariectomized, and their right ovaries were then vitrified and divided into two groups after being warmed, including vitrified-transplanted (VT) (n=11) and vitrified-encapsulated in hyaluronic acid hydrogel-transplanted (VT+HA) (n=11) that were auto transplanted into the dorsal muscle. Following that, a daily vaginal smear was obtained from the 4th day after transplantation of the rats. The ovaries were removed at the end of the first estrous cycle (approximately 15 days after transplantation), and some apoptotic genes including P53, c-Myc, Bax, Bcl-2, and Caspase 3 were evaluated by the real-time PCR. Findings: All transplants were completely successful (100%). The results also showed that the expression of the P53, c-Myc, Bax, and Caspase 3 genes were higher in the VT group, compared to the VT+HA group. However, this difference was statistically significant only in the c-Myc gene (P

الملخص: أهداف البحث: لدى العظام إمكانات محدودة للشفاء الذاتي بسبب العدوى، أو الإصابات أو الإزالة الجراحية للتكيُسات. عموما، هناك حاجة للتدخل الخارجي لزيادة إصلاح العظام وتجديدها. وتهدف هذه الدراسة لإعداد هلاميات مائية من حمض الهيالورونيك معالجة ضوئيا ومتوافقة حيويا ومحملة بنانو هيدروكسي ابيتايت والكيتوزان، وذلك باستخدام نظام جديد لتنشيط الفوتونات على أساس الريبوفلافين لتطبيقات تجديد العظام. طرق البحث: تم إعداد أربع مجموعات من الهلاميات المائية معالجة بالضوء على النحو التالي: المجموعة الأولى كمجموعة ضابطة دون أي إضافات، المجموعة الثانية المحملة بالنانو هيدروكسي ابيتايت، المجموعة الثالثة المحملة بالكيتوزان والمجموعة الرابعة المحملة بكل من نانو هيدروكسي ابيتايت وكيتوزان. يتكون نظام تنشيط الفوتونات الجديد من الريبوفلافين كمنشط فوتوي، ميتاكاريل ديماثيلامينويثيل كمنشط مشارك، يتم استخدامه مع الريبوفلافين للمرة الأولى وكلوريد ثنائي الفينيل أودونيوم كمسرّع. لكل مجموعة، تم اختبار حيود الأشعة السينية، والتشكل السطحي عن طريق مسح المجهر الإلكتروني، والخصائص الميكانيكية، وامتصاص المياه (٪) وقابلية الخلايا للحياة (٪). ثم تم اختبار إمكانات العظام في نموذج أرنب وتم إجراء تقييم للقياسات النسيجية. النتائج: تم الحصول في المجموعات الأربع على هلاميات مائية معالجة بالضوء بعد وقت قصير من التشعيع لمدة ١٠ ثوان باستخدام وحدة علاج ضوء الأسنان. وكانت الهلاميات المائية المعدة قابلة للتكيف الحيوي. وزادت الإضافة المتزامنة لنانو هيدروكسي ابيتايت وكيتوزان الخصائص الميكانيكية بثلاثة أضعاف، والقدرة على تكوين العظام بمقدار ضعفين مع فارق إحصائي كبير مقارنة بمجموعة التحكم. الاستنتاجات: المركبات الهلاميات المائية المعالجة بالضوء من حمض الهيالورونيك المحملة بنانو هيدروكسي ابيتايت والكيتوزان باستخدام نظام تنشيط الفوتونات الجديد هي مواد واعدة يمكن استخدامها في تطبيقات تجديد العظام. Abstract: Objective: Self-healing of bone from damage caused by infection, trauma, or surgical removal of cysts is limited. Generally, external intervention is needed to increase bone repair and regeneration. In this study, biocompatible light-cured hyaluronic acid hydrogels loaded with nano-hydroxyapatite and chitosan were prepared using a new photoinitiating system based on riboflavin for bone regeneration applications. Method: Four light-cured hydrogel groups were prepared as follows: Group I, a control group with no additions; Group II, loaded with nano-hydroxyapatite; Group III, loaded with chitosan; and Group IV, loaded with both nano-hydroxyapatite and chitosan. The new photoinitiating system consisted of riboflavin as a photoinitiator, dimethylaminoethyl methacrylate (DMAEMA) as a coinitiator (being used with riboflavin for the first time), and diphenyliodonium chloride as an accelerator. For each group, X-ray-diffraction, surface morphology by scanning electron microscope, mechanical properties, water uptake (%), and cell viability (%) were tested. The osteogenic potential was then tested in a rabbit model, and histomorphometric assessment was conducted. Results: In the four groups, the light-cured hydrogels were obtained after a short irradiation time of 10 s using a dental light-curing unit. The prepared hydrogels were biocompatible. Simultaneous addition of nano-hydroxyapatite and chitosan increased the mechanical properties threefold and the osteogenic potential, twofold, with a statistically significant difference compared with the control group. Conclusions: Light-cured hyaluronic acid composite hydrogels loaded with nano-hydroxyapatite and chitosan—prepared by using the new photoinitiating system—are promising materials that can be used in bone regeneration applications.

Background: One of the problems after cryopreservation and ovarian tissue transplantation is ischemia followed by follicles mortality. In the present study, hyaluronic acid hydrogel was used to improve angiogenesis in vitrified ovarian tissue transplantation in rat. Materials and Methods: In this experimental study, 22 adult female rats (~8 weeks old) with normal estrous cycles were ovariectomized, then their right ovaries were vitrified and warmed into two groups without hyaluronic acid hydrogel (VT) and encapsulated with hyaluronic acid hydrogel (VT+HA) was autotransplanted into the dorsal muscle. Daily vaginal monitoring was performed until re-initiation of first full oestrus cycles. The ovaries were removed at the end of the first estrus cycle and angiogenesis genes VEGF, CD31 and CD34 evaluated by real time PCR. Data were analyzed by Mann-Whitney test and the significance level was considered P

Transdermal drug delivery is the transport of drug across the skin and into the systemic circulation. Patch is a one of transdermal device that is used to attach on skin and contains drug. The drug matrices from hyaluronic acid (HA) and graphene oxide (GO) incorporated HA hydrogel were fabricated for the release of tamoxifen citrate (TMX) as the anticancer drug under applied electrical field. The pristine HA hydrogels as the matrix and GO as the drug encapsulation host were fabricated for transdermal patch by the solution casting using citric acid as the chemical crosslinker. In vitro drug release experiment was investigated by utilizing the modified Franz-diffusion cell under the effects of crosslinking ratio, electric potential, and GO. The TMX release behaviors from the hydrogels were found to be from the three mechanisms: the pure Fickian diffusion; the anomalous or non-Fickian diffusion; and Super case II transport depending on the crosslinking conditions. The TMX diffusion and release amount from the pristine HA hydrogels were increased with smaller crosslinking ratios. With applied electrical potential, the enhanced TMX diffusion and release amount were observed when compared to that without due to the electro-repulsive force. Furthermore, the TMX diffusion from the HA hydrogel with GO as the drug encapsulation host was higher by two orders of magnitude than without GO. [Display omitted] [ABSTRACT FROM AUTHOR]

A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo. The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1(+)/CD45(-)/CD34(+)/CD44(+) cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF165, and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb.

The reactive oxygen species (ROS) are composed of highly reactive molecules, including superoxide anions ( O 2 • - ), hydrogen peroxide (H 2 O 2 ) and hydroxyl radicals. Researchers have explored the potential benefits of using hydrogel dressings that incorporate active substances to accelerate wound healing. The present investigation involved the development of a hyaluronic acid (HA) hydrogel capable of producing ROS using LED irradiation. The process of creating a composite hydrogel was created by chemically bonding Ce6 to an amide group. Our analysis revealed that the synthesized hydrogel had a well-structured amide bond, and the degree of cross-linking was assessed through swelling, enzyme stability and cytotoxicity tests. ROS production was found to be influenced by both the intensity and duration of light exposure. Furthermore, in situations where cell toxicity resulting from ROS generation in the hydrogel surpassed 70%, no detectable genotoxic consequences were evident, and antibacterial activity was confirmed to be directly caused by the destruction of bacterial membranes as a result of ROS damage. Furthermore, the utilization of the generated ROS influences the polarization of macrophages, resulting in the secretion of pro-inflammatory cytokines, which is a characteristic feature of M1 polarization. Subsequently, we validated the efficacy of a HA hydrogel that produces ROS to directly eradicate microorganisms. Furthermore, this hydrogel facilitated indirect antibacterial activity by stimulating macrophages to release pro-inflammatory cytokines. These cytokines are crucial for coordinating cell-mediated immune responses and for modulating the overall effectiveness of the immune system. Therefore, the Ce6-HA hydrogel has the potential to serve as an effective wound dressing solution for infected wounds because of its ability to produce substantial levels or a consistent supply., (© The Author(s) 2024. Published by Oxford University Press.)

This preclinical proof-of-concept study aimed to evaluate the effectiveness of secretome therapy in diabetic mice with pressure ulcers. We utilized a custom-made hyaluronic acid (HA)-based porous sponge, which was rehydrated either with normal culture medium or secretome derived from human mesenchymal stromal cells (MSCs) to achieve a hydrogel consistency. Following application onto skin ulcers, both the hydrogel-only and the hydrogel + secretome combination accelerated wound closure compared to the vehicle group. Notably, the presence of secretome significantly enhanced the healing effect of the hydrogel, as evidenced by a thicker epidermis and increased revascularization of the healed area compared to the vehicle group. Notably, molecular analysis of healed skin revealed significant downregulation of genes involved in delayed wound healing and abnormal inflammatory response in ulcers treated with the hydrogel + secretome combination, compared to those treated with the hydrogel only. Additionally, we found no significant differences in therapeutic outcomes when comparing the use of secretome from fetal dermal MSCs to that from umbilical cord MSCs. This observation is supported by the proteomic profile of the two secretomes, which suggests a shared molecular signature responsible of the observed therapeutic effects., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pier Giulio Conaldi reports financial support was provided by Sicilian Region. Cinzia Chinnici has patent #102023000019479 pending to ISMETT and Ri.MED. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Parkinson's disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson's disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products. [ABSTRACT FROM AUTHOR]

Growth factors are critical for regulating and inducing various stem cell functions. To study the effects of growth factor delivery kinetics and presentation on stem cell fate, we developed a series of heparin-containing hyaluronic acid (HyA)-based hydrogels with various degrees of growth factor affinity and retention. To characterize this system, we investigated the effect of heparin molecular weight, fractionation, and relative concentration on the loading efficiency and retention kinetics of TGFβ1 as a model growth factor. At equal concentrations, high MW heparin both loaded and retained the greatest amount of TGFβ1, and had the slowest release kinetics, primarily due to the higher affinity with TGFβ1 compared to low MW or unfractionated heparin. Subsequently, we tested the effect of TGFβ1, presented from various heparin-containing matrices, to differentiate a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs) into endothelial cells and form vascular-like networks in vitro. High MW heparin HyA hydrogels stimulated more robust differentiation of CPCs into endothelial cells, which formed vascular-like networks within the hydrogel. This observation was attributed to the ability of high MW heparin HyA hydrogels to sequester endogenously synthesized angiogenic factors within the matrix. These results demonstrate the importance of molecular weight, fractionation, and concentration of heparin on presentation of heparin-binding growth factors and their effect on stem cell differentiation and lineage specification.

We have generated a bioinspired tunable system of hyaluronic acid (HyA)-based hydrogels for Matrix-Assisted Cell Transplantation (MACT). With this material, we have independently evaluated matrix parameters such as adhesion peptide density, mechanical properties, and growth factor sequestering capacity, to engineer an environment that imbues donor cells with a milieu that promotes survival and engraftment with host tissues after transplantation. Using a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs), we demonstrated that the addition of heparin in the HyA hydrogels was necessary to coordinate the presentation of TGFβ1 and to support the trophic functions of the CPCs via endothelial cell differentiation and vascular like tubular network formation. Presentation of exogenous TGFβ1 by binding with heparin improved differentiated CPC function by sequestering additional endogenously-produced angiogenic factors. Finally, we demonstrated that TGFβ1 and heparin-containing HyA hydrogels can promote CPC survival when implanted subcutaneously into murine hind-limbs and encouraged their participation in the ensuing neovascular response, which included blood vessels that had anastomosed with the host's blood vessels.

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This study strategically incorporates epidermal growth factor (EGF) and keratinocyte growth factor (KGF) within a hyaluronic acid (HA) hydrogel to enhance corneal wound healing. The controlled release of EGF and KGF from the HA hydrogel is engineered to promote the regeneration of both the epithelial and stromal layers. Specifically, EGF plays a pivotal role in the regeneration of the epithelial layer, while KGF exhibits efficacy in the regeneration of the stromal layer. The combination of these growth factors facilitates efficient regeneration of each layer and demonstrates the capability to modulate each other's regenerative effects. The interplay between EGF and KGF provides an understanding of their cooperative influence on the dynamics of corneal wound healing. The results of this study contribute to the development of advanced strategies for corneal wound management and offer insights into the complex process of corneal regeneration. [ABSTRACT FROM AUTHOR]

Photoaging, primarily caused by ultraviolet (UV) light, is the major factor in extrinsic skin aging. Existing anti-photoaging strategies mainly focus on early sun protection or repairing damaged skin, lacking a comprehensive treatment strategy. Therefore, this study developed a dressing that actively shields against UV radiation and repairs photoaged skin, offering double protection. This study utilized exosome-like nanovesicles derived from Olea europaea leaves (OLELNVs), enhancing them into a potent core biomaterial with high-dose effects and skin-friendly, non-cytotoxic inhibition of cell aging. These nanovesicles were incorporated into a cross-linked hyaluronic acid (HA) and tannic acid (TA) hydrogel with strong UV-absorbing properties, creating the OLELNVs@HA/TA hydrogel system. In vitro and in vivo experiments demonstrated that OLELNVs@HA/TA hydrogel can effectively reduce UV-induced skin damage and promote skin repair and regeneration. Additionally, RNA-seq and clustering analysis of miR168a-5p predicted targets revealed significant down-regulation of the NF-κB signaling pathway, mediating inflammatory aging responses. Overall, the OLELNVs@HA/TA hydrogel represents a novel dual-strategy approach for clinical application in combating photoaging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH 2 ) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

• A hyaluronic acid (HA) hydrogel was used as a tumour bed marker in breast-conserving therapy. • HA hydrogel increased visibility of tumour bed compared to marking with metal clips. • Inter- and intraobserver variability of defining boost target volume were reduced. To evaluate usefulness of hyaluronic acid (HA) hydrogel as a tumour bed marker in breast conserving therapy (BCT). To analyze inter- (Inter-OV) and intraobserver (Intra-OV) variability of contouring boost target volume (CTV boost) in external beam radiotherapy (EBRT). Thirty-two patients in the HA group and 30 patients in the control group with an early stage breast cancer were included in the study. During the surgery 1–3 ml of HA hydrogel was injected into breast to mark the tumour bed for every patient in the HA group. Moreover, surgical clips were placed underneath the lumpectomy cavity. Patients in the control group were marked only by metal markers. Three radiation oncologists delineated CTV boost twice for every patient. Three parameters were calculated to quantify contouring variability: coefficient of variation for volumes (COV V), center of mass displacement (CoMd) and conformity index (CI). There were no significant differences between mean values of COV V for HA and control group, neither for Intra-OV (0.14 vs 0.13) nor Inter-OV (0.19 vs 0.18) calculations. The mean CoMd were 6.1 mm and 9.1 mm for Inter-OV calculations and 3.9 mm and 6.4 mm for Intra-OV in the HA and the control group respectively. The mean CI for Intra-OV improved from 0.61 to 0.65 and from 0.47 to 0.56 for Inter-OV in the control and HA group respectively. HA hydrogel used as a tumour bed marker improves tumour bed visibility and reduces inter- and intraobserver variability of EBRT boost target volume delineations. [ABSTRACT FROM AUTHOR]

Based on our previous study, the utilization of an ultraviolet light photo-cross-linkable hyaluronic acid (HA) hydrogel integrated with a small molecule kartogenin-encapsulated nanoparticles obtained good reconstruction of osteochondral defects in a rabbit model, indicating the superiority of injectable hydrogel-based scaffolds in cartilage tissue engineering. Platelet-rich plasma (PRP), rich in various growth factors, proteins and cytokines, is considered to facilitate cartilage healing by stimulating cell proliferation and inducing chondrogenesis in cartilage defect site. The aim of this study was to test the therapeutic feasibility of autologous PRP combined with injectable HA hydrogel on cartilage repair. The focal cartilage defects with different critical sizes in the medial femoral condyle of a porcine model were used. At 6 months, the minipigs were sacrificed for assessment of macroscopic appearance, magnetic resonance imaging, micro-computed tomography, histology staining and biomechanics. The HA hydrogel combined with PRP-treated group showed more hyaline-like cartilage exhibited by macroscopic appearance and histological staining in terms of extracellular matrix and type II collagen without formation of hypertrophic cartilage, indicating its capacity to improve cartilage healing in the minipig model evaluated at 6 months, with full-thickness cartilage defect of 8.5 mm diameter and osteochondral defect of 6.5 mm diameter, 5 mm depth exhibiting apparent regeneration. [ABSTRACT FROM AUTHOR]

Despite the importance of the tumor microenvironment in regulating tumor progression, few in vitro models have been developed to understand the effects of non‐neoplastic cells and extracellular matrix (ECM) on drug resistance in glioblastoma (GBM) cells. Using CellTrace‐labeled human GBM and microglial (MG) cells, we established a 2D co‐culture including various ratios of the two cell types. Viability, proliferation, migration, and drug response assays were carried out to assess the role of MG. A 3D model was then established using a hyaluronic acid‐gelatin hydrogel to culture a mixture of GBM and MG and evaluate drug resistance. A contact co‐culture of fluorescently labeled GBM and MG demonstrated that MG cells modestly promoted tumor cell proliferation (17%‐30% increase) and greater migration of GBM cells (>1.5‐fold increase). Notably, the presence of MG elicited drug resistance even when in a low ratio (10%‐20%) relative to co‐cultured tumor cells. The protective effect of MG on GBM was greater in the 3D model (>100% survival of GBM when challenged with cytotoxics). This new 3D human model demonstrated the influence of non‐neoplastic cells and matrix on chemoresistance of GBM cells to three agents with different mechanisms of action suggesting that such sophisticated in vitro approaches may facilitate improved preclinical testing. [ABSTRACT FROM AUTHOR]

[Display omitted] An amine derivative of hyaluronic acid (HA) was crosslinked to obtain a 3D dried sponge. The sponge was subsequently rehydrated using secretome from human mesenchymal stromal cells (MSCs), resulting in the formation of a hydrogel. The release kinetics analysis demonstrated that the hydrogel effectively sustained secretome release, with 70% of the initially loaded wound-healing-associated cytokines being released over a 12-day period. Tuning the hydrogel properties through heparin crosslinking resulted in a biomaterial with a distinct mechanism of action. Specifically, the presence of heparin enhanced water uptake capacity of the hydrogel and increased its sensitivity to enzymatic degradation. Notably, the heparin crosslinking also led to a significant retention of cytokines within the hydrogel matrix. Overall, the secretome-rehydrated HA hydrogel holds promise as a versatile device for regenerative medicine applications: the non-heparinized hydrogel may function as a biomaterial with low reabsorption rates, sustaining the release of bioactive molecules contained in MSC secretome. In contrast, the heparinized hydrogel may serve as a depot of bioactive molecules with faster reabsorption rates. Given its patch-like characteristic, the HA-based hydrogel appears suitable as topical treatment for external organs, such as the skin. [ABSTRACT FROM AUTHOR]

Scaffolds of recombinant spider silk protein (spidroin) and hyaluronic acid (HA) hydrogel hold promise in combination with cell therapy for spinal cord injury. However, little is known concerning the human immune response to these biomaterials and grafted human neural stem/progenitor cells (hNPCs). Here, we analyzed short- and long-term in vitro activation of immune cells in human peripheral blood mononuclear cells (hPBMCs) cultured with/without recombinant spidroins, HA hydrogels, and/or allogeneic hNPCs to assess potential host–donor interactions. Viability, proliferation and phenotype of hPBMCs were analyzed using NucleoCounter and flow cytometry. hPBMC viability was confirmed after exposure to the different biomaterials. Short-term (15 h) co-cultures of hPBMCs with spidroins, but not with HA hydrogel, resulted in a significant increase in the proportion of activated CD69+ CD4+ T cells, CD8+ T cells, B cells and NK cells, which likely was caused by residual endotoxins from the Escherichia coli expression system. The observed spidroin-induced hPBMC activation was not altered by hNPCs. It is resource-effective to evaluate human compatibility of novel biomaterials early in development of the production process to, when necessary, make alterations to minimize rejection risk. Here, we present a method to evaluate biomaterials and hPBMC compatibility in conjunction with allogeneic human cells.

Adipose mesenchymal stem cell (ADMSC)-derived exosomes (ADMSC-Exos) have shown great potential in regenerative medicine and been evidenced benefiting wound repair such as burns. However, the low yield, easy loss after direct coating, and no suitable loading system to improve their availability and efficacy hinder their clinical application for wound healing. And few studies focused on the comparison of biological functions between exosomes derived from different culture techniques, especially in exosome-releasing hydrogel system. Therefore, we designed a high-performance exosome controllable releasing hydrogel system for burn wound healing, namely loading 3D-printed microfiber culture-derived exosomes in a highly biocompatible hyaluronic acid (HA). In this project, we compared the biological functions in vitro and in a burn model among exosomes derived from the conventional two-dimensional (2D) plate culture (2D-Exos), microcarrier culture (2.5D-Exos), and 3D-printed microfiber culture (3D-Exos). Results showed that compared with 2D-Exos and 2.5D-Exos, 3D-Exos promoted HACATs and HUVECs cell proliferation and migration more significantly. Additionally, 3D-Exos had stronger angiogenesis-promoting effects in tube formation of (HUVECs) cells. Moreover, we found HA-loaded 3D-Exos showed better burn wound healing promotion compared to 2D-Exos and 2.5D-Exos, including accelerated burn wound healing rate and better collagen remodeling. The study findings reveal that the HA-loaded, controllable-release 3D-Exos repair system distinctly augments therapeutic efficacy in terms of wound healing, while concurrently introducing a facile application approach. This system markedly bolsters the exosomal loading efficiency, provides a robust protective milieu, and potentiates the inherent biological functionalities of the exosomes. Our findings provide a rationale for more efficient utilization of high-quality and high-yield 3D exosomes in the future, and a novel strategy for healing severe burns., (© The Author(s) 2024. Published by Oxford University Press.)

Stem cell-derived extracellular vesicles (EVs) show great potential for promoting bone tissue regeneration. However, normal EVs (Nor-EVs) have a limited ability to direct tissue-specific regeneration. Therefore, it is necessary to optimize the osteogenic capacity of EV-based systems for repairing extensive bone defects. Herein, we show that hydrogels loaded with osteoinductive dental pulp stem cell-derived EVs (Ost-EVs) enhanced bone tissue remodeling, resulting in a 2.23 ± 0.25-fold increase in the expression of bone morphogenetic protein 2 (BMP2) compared to the hydrogel control group. Moreover, Ost-EVs led to a higher expression of alkaline phosphatase (ALP) (1.88 ± 0.16 of Ost-EVs relative to Nor-EVs) and the formation of orange-red calcium nodules (1.38 ± 0.10 of Ost-EVs relative to Nor-EVs) in vitro . RNA sequencing revealed that Ost-EVs showed significantly high miR-1246 expression. An ideal hydrogel implant should also adhere to surrounding moist tissues. In this study, we were drawn to mussel-inspired adhesive modification, where the hydrogel carrier was crafted from hyaluronic acid (HA) and polyethylene glycol derivatives, showcasing impressive tissue adhesion, self-healing capabilities, and the ability to promote bone growth. The modified HA (mHA) hydrogel was also responsive to environmental stimuli, making it an effective carrier for delivering EVs. In an ectopic osteogenesis animal model, the Ost-EV/hydrogel system effectively alleviated inflammation, accelerated revascularization, and promoted tissue mineralization. We further used a rat femoral condyle defect model to evaluate the in situ osteogenic ability of the Ost-EVs/hydrogel system. Collectively, our results suggest that Ost-EVs combined with biomaterial-based hydrogels hold promising potential for treating bone defects.

The management of chronic wounds in diabetes remains challenging due to the complexity of impaired wound healing, delayed healing, susceptibility to infection, and elevated risk of reopening, highlighting the need for effective chronic wound management with innovative approaches such as multifunctional hydrogels. Here, we have produced HA-DA@rhCol hydrogels consisting of dopamine-modified hyaluronic acid and recombinant human collagen type-III (rhCol) by oxidative coupling of the catechol group using the H 2 O 2 /HRP catalytic system. The post-reactive hydrogel has a good porous structure, swelling rate, reasonable degradation, rheological and mechanical properties, and the catechol group and dopamine impart to the hydrogel tissue adhesiveness, antioxidant capacity, and excellent photothermal effects leading to superior in vitro antimicrobial activity. In addition, the ability of rhCol to confer hydrogels to promote angiogenesis and wound repair has also been investigated. Cytotoxicity and hemolysis tests demonstrated the good biocompatibility of the hydrogel. Wound closure, collagen deposition and immunohistochemical examination confirmed the ability of the hydrogel to promote diabetic wound healing. In summary, the adhesive hemostatic antioxidative hydrogel with rhCol to promote wound healing in diabetic rat is an excellent chronic wound dressing., (© 2024 The Authors.)

Heart failure has a five-year mortality rate approaching 50%. Inducing angiogenesis following a myocardial infarction is hypothesized to reduce cardiomyocyte death and tissue damage, thereby preventing heart failure. Herein, a novel nano-in-gel delivery system for vascular endothelial growth factor (VEGF), composed of star-shaped polyglutamic acid-VEGF nanoparticles in a tyramine-modified hyaluronic acid hydrogel (nano-VEGF-HA-TA), is investigated. The ability of the nano-VEGF-HA-TA system to induce angiogenesis is assessed in vivo using a chick chorioallantoic membrane model (CAM). The formulation is then integrated with a custom-made, clinically relevant catheter suitable for minimally invasive endocardial delivery and the effect of injection on hydrogel properties is examined. Nano-VEGF-HA-TA is biocompatible on a CAM assay and significantly improves blood vessel branching (p < 0.05) and number (p < 0.05) compared to a HA-TA hydrogel without VEGF. Nano-VEGF-HA-TA is successfully injected through a 1.2 m catheter, without blocking or breaking the catheter and releases VEGF for 42 days following injection in vitro. The released VEGF retains its bioactivity, significantly improving total tubule length on a Matrigel® assay and human umbilical vein endothelial cell migration on a Transwell® migration assay. This VEGF-nano in a HA-TA hydrogel delivery system is successfully integrated with an appropriate device for clinical use, demonstrates promising angiogenic properties in vivo and is suitable for further clinical translation.

Thiolated hyaluronic acid can be combined with poly-(ethylene glycol)-diacrylate to generate a self-polymerizing hydrogel with potential applications as an injectable depot for targeted drug delivery. There is a specific need for formulations that can incorporate and control the delivery of protein-based biologics over time. In this investigation, the incorporation and release of recombinant human granulocyte macrophage-colony stimulating factor and interleukin-4 from a commercial hyaluronic acid-based hydrogel was initially examined. The release profile was rapid; essentially complete within the first 4–24 h. However, addition of a glutathione-s-transferase-tag to these cytokines reduced their initial bolus release and extended the retention to more than three days. Hypothesizing a direct interaction of the glutathione-s-transferase-tag with poly-(ethylene glycol)-diacrylate, we observed a concentration-dependent slowing of cytokine release and prolonged retention as poly-(ethylene glycol)-diacrylate concentration was increased. Hyaluronidase was then added to promote a controlled degradation and independently modulate release rate and duration. The effects were concentration-dependent, resulting in a flexible hydrogel platform in which loading and release can be independently adjusted to meet a range of delivery needs. When injected in vivo, a localized cytokine reservoir was created and exhibited the same features as observed in vitro. These findings identify a tunable platform for the targeted local delivery and controlled release of protein-based biologics. [ABSTRACT FROM AUTHOR]

• PDA nanoparticle was prepared by oxidative self polymerization of dopamine monomers. • Thiol-functionalized HA was prepared by EDC-NHS crosslinking chemistry. • Composite hydrogel was developed via Michael-type addition reaction. • Developed hydrogel was biocompatible and showed sustained drug release profile. • HUVECs showed enhanced cell migration and capillary tube formation in vitro. Crosslinking of polymeric network using nanoparticles by physical or chemical method to obtain hydrogel is an emerging approach. Herein, we synthesized Polydopamine (PDA) nanoparticles via oxidative self-polymerization of dopamine in water-ethanol mixture. Thiol-functionalized hyaluronic acid was developed using cysteamine and hyaluronic acid (HA-Cys) via 1-Ethyl-3-(3-Dimethylaminopropyl) Carbodiimide - N -hydroxysuccinimide (EDC-NHS) crosslinking chemistry. Developed HA-Cys conjugate was cross-linked using PDA nanoparticles via Michael-type addition reaction. Synthesized nanoparticles were monodisperse with size of 124 ± 8 nm and had spherical morphology. FTIR characterization confirmed successful synthesis of HA-Cys conjugate and subsequent crosslinking with PDA nanoparticles. Rheological characterization revealed that hydrogels were injectable in nature with good mechanical stability. Dimethyloxalylglycine (DMOG) loaded PDA nanoparticle showed sustained drug release for period of 7 days from composite hydrogel. Hydrogel microenvironment facilitated enhanced endothelial cell migration, proliferation and attachment. Furthermore, in response to release of DMOG from developed hydrogel, cells showed enhanced capillary tube formation in vitro. Overall, these results demonstrate that PDA cross-linked thiol-functionalized hydrogel was developed in a facile manner under physiological conditions. These developed hydrogels could be potentially used in tissue engineering and drug delivery. [ABSTRACT FROM AUTHOR]

Peptide and protein drugs, such as epidermal growth factor (EGF), face challenges related to stability and bioavailability. Recently, hydrogels have emerged as promising carriers for these drugs. This study focuses on a light-responsive hydrogel-based drug delivery system for the controlled release of EGF in wound healing. A photocleavable (PC) linker was designed to bind EGF to the hydrogel matrix, enabling UV light-triggered release of EGF. Hydrogels have evolved from drug reservoirs to controlled release systems, and the o-nitrobenzyl-based PC linkers offer selective cleavage under UV irradiation. We used a thiol-ene crosslinked hyaluronic acid (HA) hydrogel matrix modified with the PC-linked EGF. The release of EGF from the HA hydrogel under UV irradiation was evaluated, along with in vitro and in vivo experiments to assess the controlled effect of EGF on wound healing. Our results indicate that the successful development of a light-responsive hydrogel-based system for precise temporal release of EGF enhances the therapeutic potential in wound healing. This study highlights the importance of incorporating stimulus-responsive functionalities into hydrogel-based drug delivery systems to optimize protein drugs in clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Menopausal and postmenopausal women often experience vaginal atrophy due to estrogen deficiency. Mesenchymal stem cell exosomes have emerged as potential therapeutic agents, capable of promoting tissue regeneration and repair., Objective: This study aimed to explore the benefits of exosomes on VK2 cells and the therapeutic effect of topical exosomal hydrogel on atrophic vaginas., Methods: Exosomes were extracted using the high-speed centrifugation method, and their effects on VK2 cell proliferation, migration, and differentiation were observed through co-culture. The menopause model was induced by ovariectomy in rats, followed by the injection of exosome-loaded hydrogel into their vaginas. The treatment's effectiveness was evaluated by measuring vaginal epithelium thickness using HE staining, and assessing vaginal mucosa proliferation and lamina propria angiogenesis using Ki67 and anti-CD31 staining, respectively., Results: Exosomes significantly promoted VK2 cell proliferation and migration, but had no significant effect on differentiation. The exosome hydrogel increased the expression of Ki67 and CD31, leading to a significant improvement in epithelial thickness., Conclusions: UcMSC- ex can stimulate the proliferation and migration of VK2 cells, but do not appear to promote differentiation. Topical application of exosome hydrogel enhances vaginal epithelium thickness to a certain degree, offering a promising non-hormonal therapeutic strategy to alleviate vaginal atrophy in postmenopausal women.

Traumatic spinal cord injury results in permanent and serious neurological impairment, but there is no effective treatment yet. Tissue engineering approaches offer great potential for the treatment of SCI, but spinal cord complexity poses great challenges. In this study, the composite scaffold consists of a hyaluronic acid-based hydrogel, decellularized brain matrix (DBM), and bioactive compounds such as polydeoxyribonucleotide (PDRN), tumor necrosis factor-α/interferon-γ primed mesenchymal stem cell-derived extracellular vesicles (TI-EVs), and human embryonic stem cell-derived neural progenitor cells (NPC). The composite scaffold showed significant effects on regenerative prosses including angiogenesis, anti-inflammation, anti-apoptosis, and neural differentiation. In addition, the composite scaffold (DBM/PDRN/TI-EV/NPC@Gel) induced an effective spinal cord regeneration in a rat spinal cord transection model. Therefore, this multimodal approach using an integrated bioactive scaffold coupled with biochemical cues from PDRN and TI-EVs could be used as an advanced tissue engineering platform for spinal cord regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: This study aimed to identify host cell recruitment patterns in a mouse model in response to rhBMP-2 releasing hyaluronic acid hydrogels and influence of added nano-hydroxyapatite particles on rhBMP-2 release and pattern of bone formation. Materials & methods: Implanted gels were retrieved after implantation and cells were enzymatically dissociated for flow cytometric analysis. Percentages of macrophages, progenitor endothelial cells and putative mesenchymal stem cells were measured. Implants were evaluated for BMP-2 release by ELISA and by histology to monitor tissue formation. Results & conclusion: Hyaluronic acid+BMP-2 gels influenced the inflammatory response in the bone healing microenvironment. Host-derived putative mesenchymal stem cells were major contributors. Addition of hydroxyapatite nanoparticles modified the release pattern of rhBMP-2, resulting in enhanced bone formation. [ABSTRACT FROM AUTHOR]

Effective and sustained release formulations of antimetabolite 5-Flurouracil (5Fu) for ocular fibrosis are highly desirable for success of glaucoma filtration surgery (GFS). However, burst release and rapid clearance of carriers and/or drug still exist as major limitations. Here, we report the feasibility of encapsulating 5Fu in sustained release carrier of poly (d,l-lactide-co-glycolide) (PLGA) microspheres (MPs) and impregnating in a hyaluronic acid (HA) hydrogel as unit dose formulation. In order to optimize the encapsulation process by solid-in-oil-in-water emulsion technique, the effects of PLGA end groups, PLGA concentration, and 5Fu loading were studied systematically. The MPs were extensively characterized for surface morphology, particle size distribution, thermal properties, crystallinity, residual solvent, syringeability, and in vitro release. The optimized formulation of MPs was ~94 μm in size and released 5Fu in a sustained manner for up to two weeks. In our concept, MPs are dispersed first in HA solution and then cross-linked in situ after injection into the conjunctival space. Thus, syringeability experiments were also carried out with 5Fu-loaded MPs and 0.5% HA solution. To further prolong 5Fu release, a derivatized HA with methacrylic anhydride was photocross-linked along with 5Fu-loaded PLGA MPs to develop the composite hydrogel formulation. Our experimental results show that 5Fu release can be effectively controlled by PLGA MPs-loaded HA composite hydrogel for longer therapeutic benefits. These composite hydrogel systems improve the ocular residence time of the carrier and the drug, and hence could be potentially explored as injectable unit dose formulation for GFS.

Effective and sustained release formulations of antimetabolite 5-Flurouracil (5Fu) for ocular fibrosis are highly desirable for success of glaucoma filtration surgery (GFS). However, burst release and rapid clearance of carriers and/ or drug still exist as major limitations. Here, we report the feasibility of encapsulating 5Fu in sustained release carrier of poly (d,l-lactide-co-glycolide) (PLGA) microspheres (MPs) and impregnating in a hyaluronic acid (HA) hydrogel as unit dose formulation. In order to optimize the encapsulation process by solid-in-oil-in-water emulsion technique, the effects of PLGA end groups, PLGA concentration, and 5Fu loading were studied systematically. The MPs were extensively characterized for surface morphology, particle size distribution, thermal properties, crystallinity, residual solvent, syringeability, and in vitro release. The optimized formulation of MPs was ~94 μm in size and released 5Fu in a sustained manner for up to two weeks. In our concept, MPs are dispersed first in HA solution and then cross-linked in situ after injection into the conjunctival space. Thus, syringeability experiments were also carried out with 5Fu-loaded MPs and 0.5% HA solution. To further prolong 5Fu release, a derivatized HA with methacrylic anhydride was photocross-linked along with 5Fu-loaded PLGA MPs to develop the composite hydrogel formulation. Our experimental results show that 5Fu release can be effectively controlled by PLGA MPs-loaded HA composite hydrogel for longer therapeutic benefits. These composite hydrogel systems improve the ocular residence time of the carrier and the drug, and hence could be potentially explored as injectable unit dose formulation for GFS. [ABSTRACT FROM AUTHOR]

This study investigates the effect of hyaluronic acid (HA) containing VEGF and bFGF on restoration of ovarian function after ovarian autotransplantation. Twenty-four rats were randomly divided into three groups for ovarian autotransplantation: group A (ovaries without HA, VEGF and bFGF), group B (ovaries encapsulated with HA) and group C (ovaries encapsulated with HA containing VEGF and bFGF). The grafts were assessed using vaginal smears, histological, hormonal, and the genes expression analysis. The duration of first estrous cycle was shorter in group C than in group A (p < 0.01). The mean number of primordial follicles was protected in group C. The level of estradiol was higher in group A than in group C (p < 0.01). The expression level of Cellular-Myelocytomatosis (C-Myc)in group C was lower than in group B (p < 0.05). HA containing VEGF and bFGF can ensure follicular survival, decrease apoptosis and recover ovarian function after auto-transplantation. [ABSTRACT FROM PUBLISHER]

Intimal hyperplasia (IH) is the major cause of grafted vessel occlusion and occurs frequently after bypass intervention. No pharmaceutical formulation is currently available to prevent this pathology. Local perivascular delivery of an appropriate active compound released in a time-dependent manner (from day one up to 4 weeks) is necessary for an efficient single-administration preventive therapy. To this aim, we propose the combination of gel and microparticles delivery system containing atorvastatin (ATV). The incorporation of ATV in a cross-linked hyaluronic acid gel, provided in vitro a fast release over 3 days, while ATV-loaded poly-lactic- co -glycolic acid (PLGA) microparticles dispersed in the gel gave a sustained release over 4 weeks. In vivo , ATV formulations were applied perivascularly in mice undergoing carotid artery ligation. IH was significantly reduced (‐ 68%) in presence of ATV incorporated in hyaluronic acid gel and encapsulated in microparticles compared to control. No significant IH alteration was observed when ATV was incorporated only in the gel (fast release) or only in the microparticles (slow release) demonstrating that a biphasic release of ATV is essential to interfere with the development of IH. ATV was detected in adjacent tissues 28 days after the intervention, showing the sustained presence of the drug in vivo . After four weeks ATV was not detected in remote tissues, except at a very low concentration (0.044 ng/mg) in the liver, suggesting a very low risk of systemic toxicity of locally delivered ATV. Additionally, the ex vivo data showed that ATV in solution permeates through isolated human saphenous veins and thus is a good candidate for perivascular delivery. Our data demonstrate that a local biphasic ATV release on the mice ligated carotid efficiently prevents the development of IH without apparent toxicity. [ABSTRACT FROM AUTHOR]

A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo . The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1 + /CD45 − /CD34 + /CD44 + cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF 165 , and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) hydrogel has been used as a carrier of recombinant human bone morphogenetic protein (rhBMP)-2 for sustained delivery. To enhance peri-implant osteogenesis, a dried coating of rhBMP-2 HA hydrogel (BMP-HAH) on dental implants was designed; this approach provides the advantage of omitting in situ preparation of wet HA hydrogel. Sustained release of rhBMP-2 was more efficient for dried hydrogel over wet hydrogel. For both types, the released rhBMP-2 consistently led to enhanced alkaline phosphatase activity and osterix expression in human mesenchymal stromal cells. Histomorphometric analysis 4 weeks after placement of a dental implant in canine mandibles showed that the dried coating of BMP-HAH (10 μg/ml, n = 6) resulted in a significantly greater bone area (BA) than the wet BMP-HAH (10 μg/ml, n = 6) ( p = 0.006) and implants without any coating ( n = 6) ( p = 0.022), while simple dip coating with rhBMP-2 (10 μg/ml, n = 6) resulted in significantly greater BA than the other three groups ( p < 0.0005). Bone-to-implant contact (BIC) was significantly different only between the dried and wet coating of BMP-HAH ( p = 0.014). Our results suggest that a simple dip coating of rhBMP-2 is more effective for increased peri-implant osteogenesis compared to a coating of BMP-HAH with sustained release. [ABSTRACT FROM AUTHOR]