Microneedle Patch for Transdermal Sequential Delivery of KGF-2 and aFGF to Enhance Burn Wound Therapy.

Severe burn wounds usually destroy key cells' functions of the skin resulting in delayed re-epithelization and wound regeneration. Promoting key cells' activities is crucial for burn wound repair. It is well known that keratinocyte growth factor-2 (KGF-2) participates in the proliferation and morphogenesis of epithelial cells while acidic fibroblast growth factor (aFGF) is a key mediator for fibroblast and endothelial cell growth and differentiation. However, thick eschar and the harsh environment of a burn wound often decrease the delivery efficiency of fibroblast growth factor (FGF) to the wound site. Therefore, herein a novel microneedle patch for sequential transdermal delivery of KGF-2 and aFGF is fabricated to enhance burn wound therapy. aFGF is first loaded in the nanoparticle (NPaFGF) and then encapsulated NPaFGF with KGF-2 in the microneedle patch (KGF-2/NPaFGF@MN). The result shows that KGF-2/NPaFGF@MN can successfully get across the eschar and sequentially release KGF-2 and aFGF. Additional data demonstrated that KGF-2/NPaFGF@MN achieved a quicker wound closure rate with reduced necrotic tissues, faster re-epithelialization, enhanced collagen deposition, and increased neo-vascularization. Further evidence suggests that improved wound healing is regulated by significantly elevated expressions of hypoxia-inducible factor-1 alpha (HIF-1ɑ) and heat shock protein 90 (Hsp90) in burn wounds. All these data proved that KGF-2/NPaFGF@MN is an effective treatment for wound healing of burns.

Biomaterial-Based Sustained-Release Drug Formulations for Localized Cancer Immunotherapy.

Cancer immunotherapy has revolutionized clinical cancer treatments by taking advantage of the immune system to selectively and effectively target and kill cancer cells. However, clinical cancer immunotherapy treatments often have limited efficacy and/or present severe adverse effects associated primarily with their systemic administration. Localized immunotherapy has emerged to overcome these limitations by directly targeting accessible tumors via local administration, reducing potential systemic drug distribution that hampers drug efficacy and safety. Sustained-release formulations can prolong drug activity at target sites, which maximizes the benefits of localized immunotherapy to increase the therapeutic window using smaller dosages than those used for systemic injection, avoiding complications of frequent dosing. The performance of sustained-release formulations for localized cancer immunotherapy has been validated preclinically using various implantable and injectable scaffold platforms. This review introduces the sustained-release formulations developed for localized cancer immunotherapy and highlights their biomaterial-based platforms for representative classes, including inorganic scaffolds, natural hydrogels, synthetic hydrogels, and microneedle patches. The design rationale and other considerations are summarized for further development of biomaterials for the construction of optimal sustained-release formulations.

Drug cross-linking electrospun fiber for effective infected wound healing.

The management of infected wounds is still an intractable challenge in clinic. Development of antibacterial wound dressing is of great practical significance for wound management. Herein, a natural-derived antibacterial drug, tannic acid (TA), was incorporated into the electrospun polyvinyl alcohol (PVA) fiber (TA/PVA fiber, 952 ± 40 nm in diameter). TA worked as a cross-linker via hydrogen bonding with PVA to improve the physicochemical properties of the fiber and to reach a sustained drug release (88% release of drug at 48 h). Improved mechanical property (0.8-1.2 MPa) and computational simulation validated the formation of the hydrogen bonds between TA and PVA. Moreover, the antibacterial and anti-inflammatory characteristics of TA laid the foundation for the application of TA/PVA fiber in repairing infected wounds. Meanwhile, in vitro studies proved the high hemocompatibility and cytocompatibility of TA/PVA fiber. Further in vivo animal investigation showed that the TA/PVA fiber promoted the repair of infected wound by inhibiting the bacterial growth, promoting granulation formation, and collagen matrix deposition, accelerating angiogenesis, and inducing M2 macrophage polarization within 14 days. All the data demonstrated that the TA cross-linked fiber would be a potent dressing for bacteria-infected wound healing.

Advances for the treatment of lower extremity arterial disease associated with diabetes mellitus.

Lower extremity arterial disease (LEAD) is a major vascular complication of diabetes. Vascular endothelial cells dysfunction can exacerbate local ischemia, leading to a significant increase in amputation, disability, and even mortality in patients with diabetes combined with LEAD. Therefore, it is of great clinical importance to explore proper and effective treatments. Conventional treatments of diabetic LEAD include lifestyle management, medication, open surgery, endovascular treatment, and amputation. As interdisciplinary research emerges, regenerative medicine strategies have provided new insights to treat chronic limb threatening ischemia (CLTI). Therapeutic angiogenesis strategies, such as delivering growth factors, stem cells, drugs to ischemic tissues, have also been proposed to treat LEAD by fundamentally stimulating multidimensional vascular regeneration. Recent years have seen the rapid growth of tissue engineering technology; tissue-engineered biomaterials have been used to study the treatment of LEAD, such as encapsulation of growth factors and drugs in hydrogel to facilitate the restoration of blood perfusion in ischemic tissues of animals. The primary purpose of this review is to introduce treatments and novel biomaterials development in LEAD. Firstly, the pathogenesis of LEAD is briefly described. Secondly, conventional therapies and therapeutic angiogenesis strategies of LEAD are discussed. Finally, recent research advances and future perspectives on biomaterials in LEAD are proposed.

Adhesive, injectable, and ROS-responsive hybrid polyvinyl alcohol (PVA) hydrogel co-delivers metformin and fibroblast growth factor 21 (FGF21) for enhanced diabetic wound repair.

As conventional treatments for diabetic wounds often fail to achieve rapid satisfactory healing, the development of effective strategies to accelerate diabetic wound repair is highly demanded. Herein, fibroblast growth factor 21 (FGF21) and metformin co-loaded multifunctional polyvinyl alcohol (PVA) hydrogel were fabricated for improved diabetic wound healing. The in vitro results proved that the hydrogel was adhesive and injectable, and that it could particularly scavenge reactive oxygen species (ROSs), while the in vivo data demonstrated that the hydrogel could promote angiogenesis by recruiting endothelial progenitor cells (EPCs) through upregulation of Ang-1. Both ROSs' removal and EPCs' recruitment finally resulted in enhanced diabetic wound healing. This work opens a strategy approach to diabetic wound management by combining biological macromolecules and small chemical molecules together using one promising environmental modulating drug delivery system.

Latest on biomaterial-based therapies for topical treatment of psoriasis.

Psoriasis is an autoimmune inflammatory disease which is fundamentally different from dermatitis. Its treatments include topical medications and systemic drugs depending on different stages of the disease. However, these commonly used therapies are falling far short of clinical needs due to various drawbacks. More precise therapeutic strategies with minimized side effects and improved compliance are highly demanded. Recently, the rapid development of biomaterial-based therapies has made it possible and promising to attain topical psoriasis treatment. In this review, we briefly describe the significance and challenges of the topical treatment of psoriasis and emphatically overview the latest progress in novel biomaterial-based topical therapies for psoriasis including microneedles, nanoparticles, nanofibers, and hydrogels. Current clinical trials related to each biomaterial are also summarized and discussed.

Methacrylated gelatin shape-memorable cryogel subcutaneously delivers EPCs and aFGF for improved pressure ulcer repair in diabetic rat model.

Pressure ulcer (PU) in patients with diabetes mellitus (DM) is still a clinical intractable issue due to the complicated physiological characteristics by the prolonged high glucose level and impaired angiogenesis. The PU treatment includes surgical debridement, stem cell therapy and growth factors, leading to high cost and repeated professional involvement. Developing effective wound dressing combining the therapeutic cells and growth factors has become highly demanded. Herein, we reported the direct subcutaneous administration of endothelial progenitor cells (EPCs) and acid fibroblast growth factor (aFGF) with a shape-memorable methacrylated gelatin cryogel (EPCs/aFGF@GelMA) for the therapy of PU in rats with DM. This EPCs/aFGF@GelMA cryogel system presented microporous structure, elastic mechanical strength and enhanced cell migration property with controlled release of aFGF. Moreover, compared with EPCs/aFGF and GelMA alone, in vivo results showed that this EPCs/aFGF@GelMA system exhibited accelerated wound closure rate, enhanced granulation formation, collagen deposition as well as re-epithelization. Importantly, we found that the excellent positive performance of EPCs/aFGF@GelMA is due to its up-regulation of HIF-ɑ upon the wound site, modulating the microenvironment of wound site to initiate the impaired local angiogenesis. Collectively, this hybrid gelatin cryogels show great promise for biomedical applications, especially in tissue engineering and regenerative medicine.

A General Protein Unfolding-Chemical Coupling Strategy for Pure Protein Hydrogels with Mechanically Strong and Multifunctional Properties.

Protein-based hydrogels have attracted great attention due to their excellent biocompatible properties, but often suffer from weak mechanical strength. Conventional strengthening strategies for protein-based hydrogels are to introduce nanoparticles or synthetic polymers for improving their mechanical strength, but often compromise their biocompatibility. Here, a new, general, protein unfolding-chemical coupling (PNC) strategy is developed to fabricate pure protein hydrogels without any additives to achieve both high mechanical strength and excellent cell biocompatibility. This PNC strategy combines thermal-induced protein unfolding/gelation to form a physically-crosslinked network and a -NH2/-COOH coupling reaction to generate a chemicallycrosslinked network. Using bovine serum albumin (BSA) as a globular protein, PNC-BSA hydrogels show macroscopic transparency, high stability, high mechanical properties (compressive/tensile strength of 115/0.43 MPa), fast stiffness/toughness recovery of 85%/91% at room temperature, good fatigue resistance, and low cell cytotoxicity and red blood cell hemolysis. More importantly, the PNC strategy can be not only generally applied to silk fibroin, ovalbumin, and milk albumin protein to form different, high strength protein hydrogels, but also modified with PEDOT/PSS nanoparticles as strain sensors and fluorescent fillers as color sensors. This work demonstrates a new, universal, PNC method to prepare high strength, multi-functional, pure protein hydrogels beyond a few available today.

Zwitterionic Hydrogel Activates Autophagy to Promote Extracellular Matrix Remodeling for Improved Pressure Ulcer Healing.

Pressure ulcer (PU) is a worldwide problem that is hard to heal because of its prolonged inflammatory response and impaired ECM deposition caused by local hypoxia and repeated ischemia/reperfusion. Our previous study discovered that the non-fouling zwitterionic sulfated poly (sulfobetaine methacrylate) (SBMA) hydrogel can improve PU healing with rapid ECM rebuilding. However, the mechanism of the SBMA hydrogel in promoting ECM rebuilding is unclear. Therefore, in this work, the impact of the SBMA hydrogel on ECM reconstruction is comprehensively studied, and the underlying mechanism is intensively investigated in a rat PU model. The in vivo data demonstrate that compared to the PEG hydrogel, the SBMA hydrogel enhances the ECM remolding by the upregulation of fibronectin and laminin expression as well as the inhibition of MMP-2. Further investigation reveals that the decreased MMP-2 expression of zwitterionic SBMA hydrogel treatment is due to the activation of autophagy through the inhibited PI3K/Akt/mTOR signaling pathway and reduced inflammation. The association of autophagy with ECM remodeling may provide a way in guiding the design of biomaterial-based wound dressing for chronic wound repair.

Advances of Microneedles in Biomedical Applications.

A microneedle (MN) is a painless and minimally invasive drug delivery device initially developed in 1976. As microneedle technology evolves, microneedles with different shapes (cone and pyramid) and forms (solid, drug-coated, hollow, dissolvable and hydrogel-based microneedles) have been developed. The main objective of this review is the applications of microneedles in biomedical areas. Firstly, the classifications and manufacturing of microneedle are briefly introduced so that we can learn the advantages and fabrications of different MNs. Secondly, research of microneedles in biomedical therapy such as drug delivery systems, diagnoses of disease, as well as wound repair and cancer therapy are overviewed. Finally, the safety and the vision of the future of MNs are discussed.

PRMT7 targets of Foxm1 controls alveolar myofibroblast proliferation and differentiation during alveologenesis.

Although aberrant alveolar myofibroblasts (AMYFs) proliferation and differentiation are often associated with abnormal lung development and diseases, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), epigenetic mechanisms regulating proliferation and differentiation of AMYFs remain poorly understood. Protein arginine methyltransferase 7 (PRMT7) is the only reported type III enzyme responsible for monomethylation of arginine residue on both histone and nonhistone substrates. Here we provide evidence for PRMT7's function in regulating AMYFs proliferation and differentiation during lung alveologenesis. In PRMT7-deficient mice, we found reduced AMYFs proliferation and differentiation, abnormal elastin deposition, and failure of alveolar septum formation. We further shown that oncogene forkhead box M1 (Foxm1) is a direct target of PRMT7 and that PRMT7-catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) directly associate with chromatin of Foxm1 to activate its transcription, and thereby regulate of cell cycle-related genes to inhibit AMYFs proliferation and differentiation. Overexpression of Foxm1 in isolated myofibroblasts (MYFs) significantly rescued PRMT7-deficiency-induced cell proliferation and differentiation defects. Thus, our results reveal a novel epigenetic mechanism through which PRMT7-mediated histone arginine monomethylation activates Foxm1 transcriptional expression to regulate AMYFs proliferation and differentiation during lung alveologenesis and may represent a potential target for intervention in pulmonary diseases.

Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection.

Amyloid aggregation and microbial infection are considered as pathological risk factors for developing amyloid diseases, including Alzheimer's disease (AD), type II diabetes (T2D), Parkinson's disease (PD), and medullary thyroid carcinoma (MTC). Due to the multifactorial nature of amyloid diseases, single-target drugs and treatments have mostly failed to inhibit amyloid aggregation and microbial infection simultaneously, thus leading to marginal benefits for amyloid inhibition and medical treatments. Herein, we proposed and demonstrated a new "anti-amyloid and antimicrobial hypothesis" to discover two host-defense antimicrobial peptides of α-defensins containing ß-rich structures (human neutrophil peptide of HNP-1 and rabbit neutrophil peptide of NP-3A), which have demonstrated multi-target, sequence-independent functions to (i) prevent the aggregation and misfolding of different amyloid proteins of amyloid-ß (Aß, associated with AD), human islet amyloid polypeptide (hIAPP, associated with T2D), and human calcitonin (hCT, associated with MTC) at sub-stoichiometric concentrations, (ii) reduce amyloid-induced cell toxicity, and (iii) retain their original antimicrobial activity upon the formation of complexes with amyloid peptides. Further structural analysis showed that the sequence-independent amyloid inhibition function of α-defensins mainly stems from their cross-interactions with amyloid proteins via ß-structure interactions. The discovery of antimicrobial peptides containing ß-structures to inhibit both microbial infection and amyloid aggregation greatly expands the new therapeutic potential of antimicrobial peptides as multi-target amyloid inhibitors for better understanding pathological causes and treatments of amyloid diseases.

Mussel-Inspired Surface Immobilization of Heparin on Magnetic Nanoparticles for Enhanced Wound Repair via Sustained Release of a Growth Factor and M2 Macrophage Polarization.

Efficient reconstruction of a fully functional skin after wounds requires multiple functionalities of wound dressing due to the complexity of healing. In these regards, topical administration of functionalized nanoparticles capable of sustainably releasing bioactive agents to the wound site may significantly accelerate wound repair. Among the various nanoparticles, superparamagnetic iron oxide (Fe3O4) nanoparticles gain increasing attractiveness due to their intrinsic response to an external magnetic field (eMF). Herein, based on the Fe3O4 nanoparticle, we developed a fibroblast growth factor (bFGF)-loaded Fe3O4 nanoparticle using a simple mussel-inspired surface immobilization method. This nanoparticle, named as bFGF-HDC@Fe3O4, could stabilize bFGF in various conditions and exhibited sustained release of bFGF. In addition, an in vitro study discovered that bFGF-HDC@Fe3O4 could promote macrophage polarization toward an anti-inflammatory (pro-healing) M2 phenotype especially under eMF. Further, in vivo full-thickness wound animal models demonstrated that bFGF-HDC@Fe3O4 could significantly accelerate wound healing through M2 macrophage polarization and increased cell proliferation. Therefore, this approach of realizing sustained the release of the growth factor with magnetically macrophage regulating behavior through modification of Fe3O4 nanoparticles offers promising potential to tissue-regenerative applications.

Freeze-Thawing Chitosan/Ions Hydrogel Coated Gauzes Releasing Multiple Metal Ions on Demand for Improved Infected Wound Healing.

Imbalance of metal ions in the wound microenvironment is a key factor that leads to delayed wound healing. However, single metal administration to enhance wound repair is usually not enough due to the overlapping nature of the wound healing phases. Herein, a facile freeze-thawing strategy is developed to incorporate chitosan/ions hydrogel into medical gauzes to realize on-demand release of multiple ions to accelerate wound healing. In vitro study reveals that the gauzes can temporally release multiple metal ions on demand, and the released metal ions show effectiveness in killing bacteria and expediting cell migration. In vivo studies demonstrate that the metal ions loaded gauzes can efficiently enhance infected wound healing. Further histological analysis find that these metal ion-loaded gauzes accelerate wound healing by promoting granulation formation, collagen deposition and maturation, re-epithelization, angiogenesis, and inhibiting inflammation via regulating the expression of inflammatory factors (e.g., tumor necrosis factor-α) and polarization of macrophages. Thus, this novel metal ions delivery system has great potential in infected tissue repair and antibacterial applications.

Zwitterionic hydrogel for sustained release of growth factors to enhance wound healing.

Growth factors (GFs) have been well known for their therapeutic effects on wound healing. Due to their vulnerable biostability, biomaterial carriers are usually used to deliver GFs to maintain their bioactivity. Among the carriers, PEG hydrogels are the most widely applied. But the uncontrolled release of GFs and their immunogenicity dramatically retard the application of PEG hydrogels as carriers of GFs. Herein, FGF2 loaded zwitterionic sulfobetaine methacrylate (SBMA) hydrogels were developed, and it was revealed that these hydrogels were more effective in delivering FGF2 for wound healing than were PEG hydrogels. In vitro studies demonstrated that SBMA hydrogels could successfully prolong the release of FGF2, which effectively maintained the bioactivity of FGF2. Further in vivo investigation showed that SBMA hydrogels could efficiently accelerate wound regeneration by promoting granulation tissue formation, collagen deposition, cell proliferation and migration, reepithelialization and angiogenesis. All results validated that SBMA hydrogels were promising substituents of PEG hydrogels for delivering FGF2 for wound regeneration.

Highly Water-Preserving Zwitterionic Betaine-Incorporated Collagen Sponges With Anti-oxidation and Anti-inflammation for Wound Regeneration.

A core problem in wound healing - with both fundamental and technological significance - concerns the rational design of bioactive and moist microenvironments. Here, we design a new class of zwitterionic betaine-incorporated collagen sponges (BET@COL) with integrated anti-oxidation and anti-inflammatory properties for promoting wound healing in a full-thickness wound model. The presence of zwitterionic betaine in a 3D network structure of collagen enables tightly bound and locked water molecules inside sponges via ionic solvation and confinement effect, while the integration of this amino acid also empowers the sponge with anti-oxidation and anti-inflammatory functions. In vitro results demonstrated that BET@COL collagen sponges strongly preserved water content up to 33.78 ± 0.78% at the 80th min at 37°C (only 0.44 ± 0.18% in control), and also exhibited high cell biocompatibility. Further, BET@COL collagen sponges with different betaine contents were applied to a full-thickness cutaneous wound model in mice, followed by a systematical evaluation and comparison of the effect of preserved water on wound healing efficiency in vivo. The optimal BET@COL collagen sponges were able to maintain high water content (e.g., moist microenvironment), suppress oxidative stress, improve anti-inflammation, all of which impose synergetic healing effects to promote wound closure, granulation formation, re-epithelization, collagen deposition and angiogenesis. This work demonstrates a new material as a promising candidate for wound dressing.

Molecular Dynamics Simulations of Cholesterol Effects on the Interaction of hIAPP with Lipid Bilayer.

Fundamental understanding of specific interactions of human islet amyloid polypeptide (hIAPP) with cell membrane is critical for elucidating the underlying pathogenesis of type II diabetes mellitus (T2DM). Membrane cholesterol is known to regulate membrane functions and properties, but its exact role in driving hIAPP-membrane interactions still remains controversial. In this work, we computationally investigated the concentration effect of cholesterol on the adsorption, orientation, and surface interaction of hIAPP oligomers on POPC bilayers containing different amounts of cholesterol (χ = 0, 20, and 40 mol %). Collective MD simulations consistently showed that an increased cholesterol level modulated the structure and dynamics of POPC bilayer, leading to an increase of bilayer thickness, lipid packing order, and surface hydrophobicity but a decrease of lipid mobility. Cholesterol-induced bilayer changes further caused hIAPP oligomer to more preferentially bind to POPC bilayer in the presence of cholesterol via C-terminal residues, in contrast to weak or no binding of hIAPP oligomer on pure POPC bilayers. The cholesterol-enhanced hIAPP-membrane binding is mainly contributed by electrostatic interactions between C-terminal residues and lipid head groups, which may explain the rapid adsorption and aggregation of hIAPP in the presence of cholesterol in cell membranes. This computational work provides some insights into drug development and therapeutic strategies for T2DM by considering cholesterol effects.

Bioactive ECM Mimic Hyaluronic Acid Dressing via Sustained Releasing of bFGF for Enhancing Skin Wound Healing.

Successful dermal wound regeneration requires the coordination of repair cells and cellular signals with the extracellular matrix (ECM), which serves as an indispensable mechanical and biological supporter for cell functions and communications with varied cytokines during healing processes. Here, we developed an injectable bioactive wound dressing, methacrylated hyaluronic acid (Me-HA)-based hydrogel loading with basic fibroblast growth factor (bFGF), endowing the dressing with the pleiotropic bioactivity to mimic natural ECM. This bFGF@Me-HA dressing was applied to a mouse with full-thickness excisional wounds to investigate its positive roles in wound repair owing to the complementary functions of HA with sustained release of bioactive bFGF. Compared with the single Me-HA and bFGF group, bFGF@Me-HA hydrogel dressings significantly enhanced wound healing with accelerated re-epithelialization, granulation formation, collagen, deposition and skin appendage regeneration. Further investigations showed significantly promoted cell proliferation and vascularization in the bFGF@Me-HA group, which was mediated by the upregulation of transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor (VEGF) expressions. In conclusion, this bFGF@Me-HA hydrogel realized the optimization of simple ECM mimic dressing via introducing the bioactive effector, bFGF, and has the potential to be widely used as an effective bioactive ECM-based wound dressing in future wound care.

Highly Aligned Electrospun Collagen/Polycaprolactone Surgical Sutures with Sustained Release of Growth Factors for Wound Regeneration.

Development of biocompatible and bioactive drug-loaded sutures is considered as an effective but challenging strategy for the wound healing process by delivering biological drugs (e.g., antibiotics) or growth factors (e.g., bFGF) at the surgical wound sites. Conventional offline suture strategies often lead to fast and uncontrollable release of drugs at wound sites, rendering wound healing to become a longer and painful process for patients. Herein, we propose an online suture strategy to fabricate electrospun polycaprolactone (PCL) fibrous yarns, incorporated with both collagen (COL) and bFGF, to produce bFGF-COL@PCL sutures. Upon demonstrating the well-oriented and aligned fibrous microstructure, high mechanical properties, and controlled release of bFGF from bFGF-COL@PCL sutures in vitro, we then applied bFGF-COL@PCL sutures to an incision wound healing mouse model in vivo. Further in vivo study showed that as compared to the commercialized Vicryl suture, bFGF-COL@PCL sutures significantly promoted the wound healing at different stages by accelerating granulation tissue formation, collagen deposition, and re-epithelialization. The enhanced wound healing efficiency of bFGF-COL@PCL sutures is likely attributed to two synergistic factors: (i) the well-oriented nanofibrous structure reduces tissue drag to minimize their trauma and (ii) the presence of both collagen and bFGF enhances the basement membrane (BM) reconstruction, cell proliferation, and angiogenesis. This work demonstrates an effective suture strategy and system for surgical suture applications.