Enhance Skin Regeneration Research Articles

Salvianolic-Acid-B-Loaded HA Self-Healing Hydrogel Promotes Diabetic Wound Healing through Promotion of Anti-Inflammation and Angiogenesis.

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) with anti-inflammatory and pro-angiogenesis capacities for diabetic wound healing is reported. The HA hydrogel was prepared via the covalent cross-linking of aldehyde groups in oxidized HA (OHA) and hydrazide groups in adipic dihydrazide (ADH)-modified HA (HA-ADH) with the formation of reversible acylhydrazone bonds. The obtained HA hydrogel exhibited multiple favorable properties such as porous structures, excellent self-healing properties, a sustainable release capacity of SAB, as well as excellent cytocompatibility. In addition, the effects of the SAB-loaded HA self-healing hydrogel were investigated via a full-thickness skin defect model using diabetic rats. The HA/SAB hydrogel showed enhanced skin regeneration effects with accelerated wound closure, shorter remaining dermal space length, thicker granulation tissue formation, and more collagen deposition. Furthermore, reduced inflammatory response and enhanced vascularization were found with HA/SAB2.5 hydrogel-treated wounds, indicating that the hydrogel promotes diabetic wound healing through the promotion of anti-inflammation and angiogenesis. Our results suggest that the fabricated SAB-loaded HA self-healing hydrogel is promising as a wound dressing for the treatment of diabetic wounds.

Nonanimal Euglena gracilis‐Derived Extracellular Vesicles Enhance Skin‐Regenerative Wound Healing

AbstractThis study proposes using microalgae‐containing carbohydrate bioactives, an Euglena gracilis‐derived extracellular microvesicle (EMVEG) system, for enhanced skin regeneration. The critical deformation ratio, 1.67, during cell extrusion enables the authors to tune the particle size of the EMVEG at ≈1 µm, thus satisfying the encapsulation yield of β‐1,3‐glucan and the cellular delivery performance. In vitro 5‐bromo‐2'‐deoxyuridine and cell scratch assays reveal that the EMVEG promotes the proliferation and migration of skin cells, thereby increasing both collagen synthesis and the expressions of proliferation‐associated proteins. An ex vivo wound‐healing test using both artificial and porcine skin reveals that similar to that seen using β‐1,3‐glucan, the EMVEG can substantially increase the cell population, expressing the proliferation‐related protein, termed proliferating cell nuclear antigen. These results demonstrate that the EMVEG system shows considerable potential in the field of skin regeneration. This technique is expected to design new types of extracellular vesicles that are applicable for skin regeneration in the pharmaceutical and cosmetic industries.

Potential of stem cell seeded three-dimensional scaffold for regeneration of full-thickness skin wounds.

Hypoxic wounds are tough to heal and are associated with chronicity, causing major healthcare burden. Available treatment options offer only limited success for accelerated and scarless healing. Traditional skin substitutes are widely used to improve wound healing, however, they lack proper vascularization. Mesenchymal stem cells (MSCs) offer improved wound healing; however, their poor retention, survival and adherence at the wound site negatively affect their therapeutic potential. The aim of this study is to enhance skin regeneration in a rat model of full-thickness dermal wound by transplanting genetically modified MSCs seeded on a three-dimensional collagen scaffold. Rat bone marrow MSCs were efficiently incorporated in the acellular collagen scaffold. Skin tissues with transplanted subcutaneous scaffolds were histologically analysed, while angiogenesis was assessed both at gene and protein levels. Our findings demonstrated that three-dimensional collagen scaffolds play a potential role in the survival and adherence of stem cells at the wound site, while modification of MSCs with jagged one gene provides a conducive environment for wound regeneration with improved proliferation, reduced inflammation and enhanced vasculogenesis. The results of this study represent an advanced targeted approach having the potential to be translated in clinical settings for targeted personalized therapy.

Role of mesenchymal stromal cells derivatives in diabetic foot ulcers: a controlled randomized phase 1/2 clinical trial

Background: Diabetes-related foot complications have been identified as the most common isolated cause of morbidity among patients with diabetes and the leading cause of amputation. Therefore, new strategies to stimulate skin regeneration may provide a novel therapeutic approach to reduce non-healing ulcer disease. Recently, we demonstrated in proof-of-concept in humans that administration of allogeneic bone marrow mesenchymal stromal cellss derivatives (allo-hBM-MSCDs) is effective in a similar way to the use of allogeneic bone marrow mesenchymal stromal cellss (allo-hBM-MSCs) in grade 2 diabetic foot ulcers (DFUs).Aim: To assess the safety and efficacy profile of the allo-hBM-MSCDs relative to the conventional approach (PolyMen® dressing) in 1/2 clinical trial phases in patients with grade 1 and 2 DFUs.Methods: In the present study, we used 2 doses of allo-hBM-MSCDs (1 mL) or 1 dose of allo-hBM-MSCs (1 × 106 cells) intradermally injected around wounds and assessed their safety and effectiveness, relative to the conventional approach (PolyMem dressing). Allo-hBM-MSCDs and allo-hBM-MSCs were produced in a certified Good Manufacturing Practice-type Laboratory. Patients with grade 1 and 2 DFUs were randomized to receive allo-hBM-MSCDs (n=12), allo-hBM-MSCs (n=6) or conventional treatment (PolyMem dressing) (n=10). The wound-healing process was macroscopically evaluated until the complete closure of the ulcers.Results: No adverse events were reported. Patients with grade 1 and 2 DFUs treated with either allo-hBM-MSCDs or allo-hBM-MSCs, achieved greater percentages of wound closure, enhanced skin regeneration in shorter times and a greater ulcer-free survival relative to the patients who received conventional treatment. Finally, through proteomic analysis, we elucidated the proteins and growth factors that are secreted by allo-hBM-MSCs and relevant to the wound-healing process. In addition, by combining proteomics with Gene Ontology analysis, we comprehensively classified secreted proteins on both biological process and molecular function.Conclusions: In this phase 1/2 trial, our cumulative results suggest that 2 doses of allo-hBM-MSCDs combined with a wound dressing are a safe and effective treatment for grade 1 and 2 DFUs.

Restorative biodegradable two-layered hybrid microneedles for melanoma photothermal/chemo co-therapy and wound healing

Tumor killing and wound healing are two complementary and influential processes during the treatment of melanoma. Herein, a two-layered microneedle platform was developed with bifunctional effect of chemo-photothermal synergistic melanoma therapy and skin regeneration. The bifunctional platform composed of embeddable curcumin nanodrugs/new Indocyanine Green/hyaluronic acid (Cur NDs/IR820/HA) microneedles and sodium alginate/gelatin/hyaluronic acid (SA/Ge/HA) supporting backing layer was prepared through a two-step casting process. With uniform incorporation of curcumin nanodrugs and IR820, the microneedles exhibited excellent photothermal performance under external near-infrared (NIR) light stimulation and tumor co-therapy ability. Once the embeddable microneedles were inserted into skin, they would rapidly dissolve and activate drug release successfully for tumor treatment. Moreover, the SA/Ge/HA supporting backing layer was left behind to cover the wound and promote the proliferation of endothelial and fibroblasts cells for enhanced skin regeneration. The two-layered microneedles platform can simultaneously eliminate the tumor and accelerate wounding healing, which may be potentially employed as a competitive strategy for the treatment of melanoma.Graphical

PDGF-BB-derived supramolecular hydrogel for promoting skin wound healing

Chronic wounds represent a major challenge to the present healthcare system. In recent decades, many topical therapies have been investigated for the treatment of chronic wounds, including different types of wound dressings, antimicrobial agents, and cell therapy. Platelet-derived growth factor (PDGF) plays an important role in wound healing and has been approved for treatment of wounds related to diabetes mellitus. However, the high cost and short retention time of PDGF protein have limited its wide application. To overcome this challenge, we designed a PDGF-mimicking peptide by connecting PDGF epitope VRKIEIVRKK and self-assembling motif derived from β-amyloid peptide. The resultant peptide can self-assemble into a fibril-rich network and leads to supramolecular hydrogelation with good stability. The hydrophilic epitope can be exposed on the surface of nanofibrils, which might contribute to the binding and activation of PDGF receptors. The forming hydrogel is able to induce the growth and migration of vascular endothelial cells and promote the formation of vascular branches. In the full-thickness skin wounds of healthy mice, after the application of the hydrogel, the density of neovascularization marked by CD31 was greater than that in the control group on Day 3. Larger collagen deposition and a thicker epidermis were observed on Day 12. These results demonstrate that the hydrogel can stimulate collagen deposition and angiogenesis, enhance skin regeneration, and show an excellent therapeutic effect. Taken together, this work not only provides new insight into the design of bioactive peptides but also offers a promising biomaterial for wound healing.

Antimicrobial Synthetic and Natural Polymeric Nanofibers as Wound Dressing: A Review

Since ancient times, wound dressings have experienced many significant improvements. Evolution began using natural materials to merely cover wounds and advanced to used innovative techniques that can be customized to perform different impressive functions. Recent wound dressings, which are made of electrospun polymers, contain different active compounds, such as antimicrobial agents, that aid in wound healing and prevent dehydration and infection. The mentioned issues may influence the healing process, leading even to serious health risks for the patients. As a result, scientists are now working on novel wound bandages with improved antimicrobial properties. Electrospun polymeric nanofibers, because of their structural similarities to normal skin's extracellular matrix (ECM), bactericidal activity, and appropriateness to distribute bioactive molecules to the wound location, are regarded as good resources for enhancing skin regeneration and controlling wound infection. Herein, the latest findings on approaches for producing antimicrobial polymeric nanofibers using electrospinning and related processes are discussed. Recent advances in antibacterial biopolymeric nanofibers incorporating antimicrobial nanoparticles (silver, zinc oxide, copper oxide, etc.) are discussed. This review paper may raise significant issues, encourage additional research, and offer important insight into the potential area of antibacterial polymeric fibers.

Electrosprayed cefazolin-loaded niosomes onto electrospun chitosan nanofibrous membrane for wound healing applications.

Chronic wounds are among the most therapeutically challenging conditions, which are commonly followed by bacterial infection. The ideal approach to treat such injuries are synergistic infection therapy and skin tissue regeneration. In the recent decades, nanotechnology has played a critical role in eradicating bacterial infections by introducing several carriers developed for drug delivery. Moreover, advances in tissue engineering have resulted in new drug delivery systems that can improve the skin regeneration rate and quality. In this study, cefazolin-loaded niosomes were electrosprayed onto chitosan membrane for wound healing applications. For this purpose, niosomes were obtained by the thin-film hydration method; electrospinning was then conducted to fabricate nanofibrous mats. In vitro characterization of the scaffold was performed to evaluate the physicochemical and biological properties. Finally, in vivo studies were carried out to evaluate the potential use of the membrane for skin regeneration. In vitro results indicated the antibacterial properties of the membrane against Staphylococcus aureus (S.aureus) and Pseudomonas aeruginosa (P.aeruginosa) due to the gradual release of cefazolin from niosomes. The scaffolds also showed no cell toxicity. In vivo studies also confirmed the ability of the membrane to enhance skin regeneration by improving re-epithelialization, tissue remodeling, and angiogenesis. The current study could well show the promising role of the prepared scaffold for skin regeneration and bacterial infection elimination.

Functionalized chitosan/spherical nanocellulose-based hydrogel with superior antibacterial efficiency for wound healing

Cellulose nanomaterials have received significant interest due to their superior physicochemical properties and biocompatibility. The nanomaterials-based hydrogel patches are widely explored for skin regeneration. However, the injectability and adhesiveness of the hydrogels are crucial challenges for tissue engineering applications. To overcome these, we synthesized an injectable and adhesive hydrogel of spherical nanocellulose (s-NC) reinforced carboxymethyl chitosan for rapid skin regeneration. The s-NC exhibited improved cellular activity than cellulose nanocrystals. The hydrogels exhibited adhesive and injectability potentials and were molded in the desired configurations. An enhanced conductivity was observed in s-NC added hydrogels than the pure polymer hydrogel. The skin regeneration potential of the hydrogel scaffolds was also examined in the rats using the wound healing model. The composite scaffolds also showed improved antibacterial potential. Taken together, the developed hydrogels have the potential and can be explored as a promising biomaterial for enhanced skin regeneration applications.

Liquid Crystal Elastomer Metamaterials with Giant Biaxial Thermal Shrinkage for Enhancing Skin Regeneration (Adv. Mater. 45/2021)

Metamaterials In article number 2106175, Daining Fang, Yihui Zhang, and co-workers present unique mechanics-guided designs and fabrication schemes of liquid crystal elastomer metamaterials that allow access to unprecedented biaxial thermal shrinkage. A low-temperature synthesis method enables excellent actuation performance at substantially reduced temperatures. Such metamaterials are integrated with dressings to develop shrinkable, hemostatic patches for enhancing skin regeneration.

In-vitro evaluation of electrospun cellulose acetate nanofiber containing Graphene oxide/TiO2/Curcumin for wound healing application

Graphene-based dressings have gained interest in wound healing due to their biocompatibility and antimicrobial properties. This study developed a graphene oxide/TiO 2 /curcumin integrated cellulose acetate (CA) nanofiber for wound dressing applications. Electrospinning was used to fabricate the CA/GO/TiO 2 /curcumin nanofiber. The formation of CA nanofiber was clearly visible using FE-SEM. The presence of curcumin in CA/GO/TiO 2 /curcumin nanofiber was confirmed by FT-IR analysis. The prepared nanofiber was characterized by swelling, degradation, tensile strength, and in-vitro wound healing properties. CA/GO/TiO 2 /curcumin nanofiber demonstrated considerable antibacterial activity against wound pathogens and improved wound healing, as confirmed by MTT and migration assays. The fabricated CA/GO/TiO 2 /curcumin nanofiber exhibited exceptional hemocompatibility and biocompatibility. The drug release study revealed that sustained curcumin release would improve skin regeneration and wound healing. Invitro analysis confirmed that CA/GO/TiO 2 /curcumin nanofiber has the potential to be used as a wound dressing material. • Graphene oxide/TiO 2 /curcumin incorporated cellulose acetate (CA) nanofiber for wound dressing applications. • The CA/GO/TiO 2 /curcumin nanofiber was fabricated by electrospinning method. • Composite nanofibers enhances wound healing process which is confirmed by MTT and migration assay. • The sustained drug release behaviour would enhance skin regeneration. • In vitro analysis confirms that the CA/GO/TiO 2 /curcumin nanofiber is a suitable wound dressing material.

Injectable self-assembling peptide nanofiber hydrogel as a bioactive 3D platform to promote chronic wound tissue regeneration

Chronic wounds remain a worldwide clinical challenge, and bioactive materials that can promote skin regeneration are required. Self-assembling peptide (SAP) hydrogels have shown great potential in tissue repair, but their regenerative efficacy and possible mechanism in chronic wound healing are unclear. Here, we report an SAP (KGH) that enhances extracellular matrix (ECM) remodeling and angiogenesis, thereby promoting chronic wound healing in diabetic mice. In vivo, the KGH hydrogel was retained in wounds up to 7 days after injection, and it was effective in speeding up wound closure by ∼20% compared to the control groups and enhancing angiogenesis (e.g., VEGFA, CD31+ capillaries), cell proliferation (e.g., PCNA+ cells), formation of granulation tissue (e.g., α-SMA), and ECM deposition/remodeling (e.g., collagen I, fibronectin). In vitro, the KGH hydrogel created a 3D microenvironment for skin cells, maintained the sustained growth of cell spheroids, and increased the secretion of ECM proteins (e.g., laminin) and growth factors (e.g., PDGFB, VEGFA, and TGF-β) in skin keratinocytes compared to the conventional 2D culture. Mechanistically, the KGH hydrogel might promote wound tissue regeneration by activating the Rho/ROCK and TGF-β/MEK/MAPK pathways. As a type of designed material, SAP can be further re-engineered with biological motifs, therapeutic reagents, or stem cells to enhance skin regeneration. This study highlights that SAP hydrogels are a promising material platform for advanced chronic wound healing and might have translational potential in future clinical applications. Statement of significanceChronic wounds are a common and serious health issue worldwide, and bioactive dressing materials are required to address this issue. SAP hydrogels have shown certain tissue repair potential, but their regenerative efficacy and underlying mechanism in chronic wound healing remain elusive. Herein, we report that SAP hydrogels create a native 3D microenvironment that can remarkably stimulate angiogenesis and ECM remodeling in diabetic wounds. Mechanistically, the SAP hydrogel promoted ECM proteins and GFs secretion in skin cells through the activation of the Rho/ROCK and TGF-ß/MEK/MAPK pathways. Additionally, SAP can be readily engineered with various bioactive motifs or therapeutic drugs/cells. This work highlights SAP hydrogels as a promising biomaterial platform for chronic wound healing and the regeneration of many other tissues.

Delivery of Bioactive Compounds to Improve Skin Cell Responses on Microfabricated Electrospun Microenvironments.

The introduction of microtopographies within biomaterial devices is a promising approach that allows one to replicate to a degree the complex native environment in which human cells reside. Previously, our group showed that by combining electrospun fibers and additive manufacturing it is possible to replicate to an extent the stem cell microenvironment (rete ridges) located between the epidermal and dermal layers. Our group has also explored the use of novel proangiogenic compounds to improve the vascularization of skin constructs. Here, we combine our previous approaches to fabricate innovative polycaprolactone fibrous microtopographical scaffolds loaded with bioactive compounds (2-deoxy-D-ribose, 17β-estradiol, and aloe vera). Metabolic activity assay showed that microstructured scaffolds can be used to deliver bioactive agents and that the chemical relation between the working compound and the electrospinning solution is critical to replicate as much as possible the targeted morphologies. We also reported that human skin cell lines have a dose-dependent response to the bioactive compounds and that their inclusion has the potential to improve cell activity, induce blood vessel formation and alter the expression of relevant epithelial markers (collagen IV and integrin β1). In summary, we have developed fibrous matrixes containing synthetic rete-ridge-like structures that can deliver key bioactive compounds that can enhance skin regeneration and ultimately aid in the development of a complex wound healing device.

Chelidoniummajus L. Incorporated Emulsion Electrospun PCL/PVA_PEC Nanofibrous Meshes for Antibacterial Wound Dressing Applications.

Presently, there are many different types of wound dressings available on the market. Nonetheless, there is still a great interest to improve the performance and efficiency of these materials. Concerning that, new dressing materials containing natural products, such as medicinal plants that protect the wound from infections but also enhance skin regeneration have been or are being developed. Herein, we used for the first time a needleless emulsion electrospinning technique for incorporating Chelidonium majus L. (C. majus), a medicinal plant widely known for its traditional therapeutic properties, in Polycaprolactone (PCL)/Polyvinyl Alcohol (PVA)_Pectin (PEC) nanofibrous meshes. Moreover, the potential use of these electrospun nanofibers as a carrier for C. majus was also explored. The results obtained revealed that the produced PCL/PVA_PEC nanofibrous meshes containing C. majus extract displayed morphological characteristics similar to the natural extracellular matrix of the skin (ECM). Furthermore, the produced meshes showed beneficial properties to support the healing process. Additionally, the C. majus-loaded PCL/PVA_PEC nanofibrous meshes inhibited Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) growth, reaching a 3.82 Log reduction, and showed to be useful for controlled release, without causing any cytotoxic effect on the normal human dermal fibroblasts (NHDF) cells. Hence, these findings suggest the promising suitability of this novel wound dressing material for prevention and treatment of bacterial wound infections.

Collagen/glycosaminoglycan-based matrices for controlling skin cell responses.

Wound healing and tissue regeneration are orchestrated by the cellular microenvironment, e.g. the extracellular matrix (ECM). Including ECM components inbiomaterials is a promising approach for improving regenerative processes, e.g. wound healing in skin. Thisreview addresses recent findings for enhanced epidermal-dermal regenerative processes oncollagen (coll)/glycosaminoglycan (GAG)-based matrices containing sulfated GAG (sGAG) in simple and complex invitro models. These matrices comprise 2D-coatings, electrospun nanofibrous scaffolds, and photo-crosslinked acrylated hyaluronan (HA-AC)/coll-based hydrogels. They demonstrated to regulate keratinocyteand fibroblast migration and growth, to stimulate melanogenesis in melanocytes from the outer root sheath (ORS) of hair follicles and to enhance the epithelial differentiation of human mesenchymal stem cells (hMSC). The matrices' suitability for delivery of relevant growth factors, like heparin-binding epidermal growth factor like growth factor (HB-EGF), further highlights their potential as bioinspired, functional microenvironments for enhancing skin regeneration.

Electrospun PLGA/SF/artemisinin composite nanofibrous membranes for wound dressing

Combining biodegradable materials with natural plant components for wound dressing has been receiving significant attention. ART is a sesquiterpene lactone compound extracted from Artemisia annua L., possessing multiple pharmacological effects including antibacterial activity and anti-inflammatory property. Herein, the blended polylactic acid glycolic acid (PLGA)/silk fibroin (SF) membranes loaded with artemisinin (ART) are fabricated through electrospinning. With aid of SF, the fabricated membranes have a good sustained-release effect, and the accumulated ART release can reach 69% after three weeks. PLGA/SF/ART membranes exhibit favorable anti-inflammatory and cell compatibility in vitro evaluations. The in vivo experiment indicates that PLGA/SF/ART2 membranes can shorten the inflammation period and enhance skin regeneration in a full-thickness wound model through down-regulating the expressions of pro-inflammatory cytokines IL-1β and TNF-α. To sum up, the fabricated PLGA/SF/ART2 composite membranes with anti-inflammatory properties can be a proposal wound dressing for chronic wound healing.

The Development of Tissue Engineering Scaffolds Using Matrix from iPS-Reprogrammed Fibroblasts.

Tissue engineering solutions have been widely explored for enhanced healing of skin wounds. Diabetic foot ulcers (DFU) are particularly challenging wounds to heal for a variety of reasons, including aberrant ECM, dysregulation of vascularization, and persistent inflammation. Tissue engineering approaches, such as porous collagen-based scaffolds, have shown promise in replacing the current treatments of surgical debridement and topical treatments. Collagen-glycosaminoglycan scaffolds, which are FDA approved for diabetic foot ulcers, can benefit from further functionalization by incorporation of additional signaling factors or extracellular matrix molecules. One option for this is to incorporate matrix from a rejuvenated cell source, as wounds in younger patients heal more quickly. Induced pluripotent stem cells (iPS) are generated from somatic cells and share many functional similarities with embryonic stem cells (ES), while avoiding the ethical concerns. Fibroblasts differentiated from iPS cells have been shown to enrich their ECM with glycosaminoglycan (GAGs), collagen Type III and fibronectin, to have an increased ECM production, and to be pro-angiogenic. Here we describe a technique to grow matrix from post-iPS fibroblasts, and to develop a scaffold from this matrix, in combination with collagen, with the goal of enhancing wound healing. By activating scaffolds with extracellular matrix (ECM) from fibroblasts derived from an iPS source (post-iPSF), the scaffolds are enriched with beneficial elements like GAGs, collagen type III, fibronectin, and VEGF. We believe these scaffolds can enhance skin regeneration and that the techniques can be modified for other tissue engineering applications.

PDGF-mimicking supramolecular nanofibers for ionizing radiation-induced injury repair

Platelet-derived growth factors (PDGFs) play crucial roles in regulating cell proliferation, apoptosis, and migration and have been recommended for injury repair in clinical practice. However, the low stability, poor biological barrier penetration ability, and high cost of protein drugs hinders their wide application. The development of small molecules or nanomaterials capable of simulating the bioactivity of PDGFs may overcome the shortcomings of PDGF proteins and expand their application. Herein, we report the first supramolecular nanofiber of the self-assembling peptide Nap-FFGVRKKP (Compound 1) with superior bioactivity over the PDGF protein. The peptide derivative Nap-FFG formed a β-sheet conformation, which mimicks the four-β-sheet peptide in PDGF, and the pentapeptide VRKKP from loop 3 in PDGF that is crucial for binding with the PDGF receptor. Therefore, the nanofibers possessed the multivalent loop 3 peptide on the surface that might assist oligomerization and activation of the PDGF receptor. The results indicated that our nanomaterials efficiently activated the PDGF signaling pathway and promoted NIH 3T3 cell proliferation and migration. Moreover, they significantly reduced the apoptosis rate caused by 10 Gy X-ray radiation from 33.60% to 5.83% and showed a good therapeutic effect on the ionizing radiation-induced injury repair by reducing the inflammatory response and enhancing skin regeneration. Our study offers a versatile strategy to construct nanomaterials with enhanced biological activity through multivalent interactions, and the development of PDGF mimics may overcome the limitation of PDGFs for their applications in injury repair, cell culture, cosmetics, and regenerative medicine.

Mesenchymal stem cells derivatives as a novel and potential therapeutic approach to treat diabetic foot ulcers.

SummaryDiabetic foot ulcer morbidity and mortality are dramatically increasing worldwide, reinforcing the urgency to propose more effective interventions to treat such a devastating condition. Previously, using a diabetic mouse model, we demonstrated that administration of bone marrow mesenchymal stem cells derivatives is more effective than the use of bone marrow mesenchymal stem cells alone. Here, we used the aforementioned treatments on three patients with grade 2 diabetic foot ulcers and assessed their beneficial effects, relative to the conventional approach. In the present study, two doses of cell derivatives, one dose of mesenchymal stem cells or one dose of vehicle (saline solution with 5% of human albumin), were intradermally injected around wounds. Wound healing process and changes on re-epithelialization were macroscopically evaluated until complete closure of the ulcers. All ulcers were simultaneously treated with conventional treatment (PolyMen® dressing). Patients treated with either cell derivatives or mesenchymal stem cells achieved higher percentages of wound closure in shorter times, relative to the patient treated with the conventional treatment. The cell derivative and mesenchymal stem cells approaches resulted in complete wound closure and enhanced skin regeneration at some point between days 35 and 42, although no differences between these two treatments were observed. Moreover, wounds treated with the conventional treatment healed after 161 days. Intradermal administration of cell derivatives improved wound healing to a similar extent as mesenchymal stem cells. Thus, our results suggest that mesenchymal stem cell derivatives may serve as a novel and potential therapeutic approach to treat diabetic foot ulcers.Learning points:In diabetic mouse models, the administration of mesenchymal stem cells derivatives have been demonstrated to be more effective than the use of marrow mesenchymal stem cells alone.Mesenchymal stem cells have been explored as an attractive therapeutic option to treat non-healing ulcers.Mesenchymal stem cells derivatives accelerate the re-epithelialization on diabetic foot ulcers.

Multilayer Injectable Hydrogel System Sequentially Delivers Bioactive Substances for Each Wound Healing Stage.

Wound healing is a dynamic and complex process that contains several sequential phases. However, most of the current drug delivery systems were designed to treat only one certain phase of wound repair, ignoring the fact that every stage plays critical roles in the wound healing process and those critical stages coordinately work to ensure optimal tissue regeneration. Therefore, a delivery system that can precisely meet the requirements of each wound healing stage is desired to enhance tissue regeneration. In this study, an injectable sodium alginate/bioglass (SA/BG) composite hydrogel was used to carry SA microparticles containing a conditioned medium (CM) of cells (SACM). Inside the SACM microparticles, poly(lactic-co-glycolic acid) (PLGA) microspheres containing pirfenidone (PFD) were encapsulated (PLGAPFD). This multilayer injectable hydrogel system (SA/BG-SACM-PLGAPFD) was designed to sequentially deliver bioactive molecules for meeting the bioactivity requirement and timeline of each wound healing stage. First, SA/BG hydrogels could rapidly release BG ionic products in the first 1-3 days to regulate the inflammatory response of the host and initiate the subsequent tissue regeneration. Then, SACM hydrogel microparticles could release CM of RAW 264.7 cells stimulated with BG ionic products in 2-7 days to facilitate the formation of the vascularized granulation tissue. Finally, PLGAPFD microspheres released PFD in 8-20 days to prevent the fibrosis and scar formation in the regenerated skin. Thus, this SA/BG-SACM-PLGAPFD delivery system could restrain host inflammation, accelerate wound healing, and inhibit the fibrosis formation in a diabetic mouse skin damage model, enhancing skin regeneration. As the bioactive components in each layer of the system can be adjusted according to the requirements of different tissue regeneration, this three-layered injectable biomaterial system has a wide application potential in the regenerative medicine field.