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OBJECTIVE: Skin fibrosis places an enormous burden on patients and society, but disagreement exists over methods to quantify severity of skin scarring. A suction cutometer measures skin elasticity in vivo, but it has not been widely adopted because of inconsistency in data produced. We investigated variability of several dimensionless parameters generated by the cutometer to improve their precision and accuracy. APPROACH: Twenty adult human subjects underwent suction cutometer measurement of normal skin (NS) and fibrotic scars (FS). Using Mode 1, each subject underwent five trials with each trial containing four curves. R0/2/5/6/7 and Q1/2/3 data were collected. Analyses were performed on these calculated parameters. RESULTS: R0/2/5/6/7 and Q1/2 parameters from curves 1 to 4 demonstrated significant differences, whereas these same parameters were not significantly different when only using curves 2–4. Individual analysis of all parameters between curve 1 and every subsequent curve was statistically significant for R0, R2, R5, R6, R7, Q1, and Q2. No differences were appreciated for parameter Q3. Comparison between NS and FS were significantly different for parameters R5, Q1, and Q3. INNOVATION: Our study is the first demonstration of accurate comparison between NS and FS using the dimensionless parameters of a suction cutometer. CONCLUSIONS: Measured parameters from the first curve of each trial were significantly different from subsequent curves for both NS and FS. Precision and reproducibility of data from dimensionless parameters can therefore be improved by removing the first curve. R5, Q1, and Q3 parameters differentiated NS as more elastic than FS.

Objective: Osteochondral defect presents a big challenge for clinical treatment. This study aimed at constructing a bi-layered composite chitosan/chitosan-β-tricalcium phosphate (CS/CS-β-TCP) scaffold and at repairing the rat osteochondral defect. Approach: The bi-layered CS/CS-β-TCP scaffold was fabricated by lyophilization, and its microstructure was observed by a scanning electron microscope. Chondrocytes and bone marrow stem cells (BMSCs) were seeded into the CS layer and the CS-β-TCP layer, respectively. Viability and proliferation ability of the cells were observed under a confocal microscope. After subcutaneous implantation, the chondrogenic ability of the CS layer and osteogenic ability of the CS-β-TCP layer were evaluated by immunofluorescence. Then, the bi-layered scaffolds were implanted into the rat osteochondral defects and the harvested samples were macroscopically and histologically evaluated. Results: The bi-layered CS/CS-β-TCP scaffold exhibited the distinctive microstructures for each layer. The seeded chondrocytes in the CS layer could maintain the chondrogenic lineage, whereas BMSCs in the CS-β-TCP layer could continually differentiate into the osteogenic lineage. Moreover, cells in both layers could maintain well viability and excellent proliferation ability. For the in vivo study, the newly formed tissues in the bi-layered scaffolds group were similar with the native osteochondral tissues, which comprised hyaline-like cartilage and subchondral bone, with better repair effects compared with those of the pure CS group and the blank control group. Innovation: This is the first time that the bi-layered composite CS/CS-β-TCP scaffold has been fabricated and evaluated with respect to osteochondral defect repair. Conclusion: The bi-layered CS/CS-β-TCP scaffolds could facilitate osteochondral defect repair and might be the promising candidates for osteochondral tissue engineering.

Objective: One of the leading causes of death following traumatic injury is exsanguination. Biological material-based hemostatic agents such as fibrin, thrombin, and albumin have a high risk for causing infection. Synthetic peptide-based hemostatic agents offer an attractive alternative. The objective of this study is to explore the potential of h9e peptide as an effective hemostatic agent in both in vitro and in vivo models. Approach: In vitro blood coagulation kinetics in the presence of h9e peptide was determined as a function of gelation time using a dynamic rheometer. In vivo hemostatic effects were studied using the Wistar rat model. Results were compared to those of the commercial hemostatic product Celox™, a chitosan-based product. Adhesion of h9e peptide was evaluated using the platelet adhesion test. Biocompatibility of h9e peptide was studied in vivo using a mouse model. Results: After h9e peptide solution was mixed with blood, gelation started immediately, increased rapidly with time, and reached more than 100 Pa within 3 s. Blood coagulation strength increased as h9e peptide wt% concentration increased. In the rat model, h9e peptide solution at 5% weight concentration significantly reduced both bleeding time and blood loss, outperforming Celox. Preliminary pathological studies indicate that h9e peptide solution is biocompatible and did not have negative effects when injected subcutaneously in a mouse model. Innovation: For the first time, h9e peptide was found to have highly efficient hemostatic effects by forming nanoweb-like structures, which act as a preliminary thrombus and a surface to arrest bleeding 82% faster compared to the commercial hemostatic agent Celox. Conclusion: This study demonstrates that h9e peptide is a promising hemostatic biomaterial, not only because of its greater hemostatic effect than commercial product Celox but also because of its excellent biocompatibility based on the in vivo mouse model study.

Objective: Ischemic heart disease accounts for over 20% of all deaths worldwide. As the global population faces a rising burden of chronic diseases, such as hypertension, hyperlipidemia, and diabetes, the prevalence of heart failure due to ischemic heart disease is estimated to increase. We sought to develop a model that may more accurately identify therapeutic targets to mitigate the development of heart failure following myocardial infarction (MI). Approach: Having utilized fetal large mammalian models of scarless wound healing, we proposed a fetal ovine model of myocardial regeneration after MI. Results: Use of this model has identified critical pathways in the mammalian response to MI, which are differentially activated in the regenerative, fetal mammalian response to MI when compared to the reparative, scar-forming, adult mammalian response to MI. Innovation: While the foundation of myocardial regeneration research has been built on zebrafish and rodent models, effective therapies derived from these disease models have been lacking; therefore, we sought to develop a more representative ovine model of myocardial regeneration after MI to improve the identification of therapeutic targets designed to mitigate the development of heart failure following MI. Conclusions: To develop therapies aimed at mitigating this rising burden of disease, it is critical that the animal models we utilize closely reflect the physiology and pathology we observe in human disease. We encourage use of this ovine large mammalian model to facilitate identification of therapies designed to mitigate the growing burden of heart failure.

Personalized care models are dominating modern medicine. These models are rooted in teaching future physicians the skill set to keep up with innovation. In orthopedic surgery and neurosurgery, education is increasingly influenced by augmented reality, simulation, navigation, robotics, and in some cases, artificial intelligence. The postpandemic learning environment has also changed, emphasizing online learning and skill- and competency-based teaching models incorporating clinical and bench-top research. Attempts to improve work–life balance and minimize physician burnout have led to work-hour restrictions in postgraduate training programs. These restrictions have made it particularly challenging for orthopedic and neurosurgery residents to acquire the knowledge and skill set to meet the requirements for certification. The fast-paced flow of information and the rapid implementation of innovation require higher efficiencies in the modern postgraduate training environment. However, what is taught typically lags several years behind. Examples include minimally invasive tissue-sparing techniques through tubular small-bladed retractor systems, robotic and navigation, endoscopic, patient-specific implants made possible by advances in imaging technology and 3D printing, and regenerative strategies. Currently, the traditional roles of mentee and mentor are being redefined. The future orthopedic surgeons and neurosurgeons involved in personalized surgical pain management will need to be versed in several disciplines ranging from bioengineering, basic research, computer, social and health sciences, clinical study, trial design, public health policy development, and economic accountability. Solutions to the fast-paced innovation cycle in orthopedic surgery and neurosurgery include adaptive learning skills to seize opportunities for innovation with execution and implementation by facilitating translational research and clinical program development across traditional boundaries between clinical and nonclinical specialties. Preparing the future generation of surgeons to have the aptitude to keep up with the rapid technological advances is challenging for postgraduate residency programs and accreditation agencies. However, implementing clinical protocol change when the entrepreneur–investigator surgeon substantiates it with high-grade clinical evidence is at the heart of personalized surgical pain management.

Objective: High bacterial load contributes to chronicity of wounds and is diagnosed based on assessment of clinical signs and symptoms (CSS) of infection, but these characteristics are poor predictors of bacterial burden. Point-of-care fluorescence imaging (FL) MolecuLight i:X can improve identification of wounds with high bacterial burden (>104 colony-forming unit [CFU]/g). FL detects bacteria, whether planktonic or in biofilm, but does not distinguish between the two. In this study, diagnostic accuracy of FL was compared to CSS during routine wound assessment. Postassessment, clinicians were surveyed to assess impact of FL on treatment plan. Approach: A prospective multicenter controlled study was conducted by 20 study clinicians from 14 outpatient advanced wound care centers across the United States. Wounds underwent assessment for CSS followed by FL. Biopsies were collected to confirm total bacterial load. Three hundred fifty patients completed the study (138 diabetic foot ulcers, 106 venous leg ulcers, 60 surgical sites, 22 pressure ulcers, and 24 others). Results: Around 287/350 wounds (82%) had bacterial loads >104 CFU/g, and CSS missed detection of 85% of these wounds. FL significantly increased detection of bacteria (>104 CFU/g) by fourfold, and this was consistent across wound types (p

Objective: To explore the clinical efficacy and advantages of five-in-one comprehensive limb salvage technologies for the treatment of severe diabetic foot ulcer (DFU). Approach: Clinical data for 120 patients with severe DFU treated between January 2012 and December 2017 were analyzed retrospectively. The control group (48 cases) was treated with traditional therapies, including controlling blood sugar, improving microcirculation, preserving nerve function, and dressing changes, whereas the experimental group (72 cases) was treated with traditional therapy combined with additional techniques, such as early and thorough debridement, negative pressure wound therapy, revascularization, and skin graft or flap. Ankle–brachial index (ABI), transcutaneous oxygen pressure (TcPO(2)), wound healing rate, healing time, ulcer recurrence rate, and amputation rate were recorded. Results: Compared with the control group, the experimental group significantly improved wound healing rate (93.1% vs. 72.9%; p

Objective: This study evaluated the use of novel peptides derived from platelet-derived growth factor (PDGF-BB) as potential wound healing stimulants. One of the compounds (named PDGF2) was subjected for further research after cytotoxicity and proliferation assays on human skin cells. Further investigation included evaluation of: migration and chemotaxis of skin cells, immunological and allergic safety, the transcriptional analyses of adipose-derived stem cells (ASCs) and dermal fibroblasts stimulated with PDGF2, and the use of dorsal skin wound injury model to evaluate the effect of wound healing in mice. Approach: Colorimetric lactate dehydrogenase and tetrazolium assays were used to evaluate the cytotoxicity and the effect on proliferation. PDGF2 effect on migration and chemotaxis was also checked. Immunological safety and allergic potential were evaluated with a lymphocyte activation and basophil activation test. Transcriptional profiles of ASCs and primary fibroblasts were assessed after stimulation with PDGF2. Eight-week-old BALB/c female mice were used for dorsal skin wound injury model. Results: PDGF2 showed low cytotoxicity, pro-proliferative effects on human skin cells, high immunological safety, and accelerated wound healing in mouse model. Furthermore, transcriptomic analysis of ASCs and fibroblasts revealed the activation of processes involved in wound healing and indicated its safety. Innovation: A novel peptide derived from PDGF-BB was proved to be safe drug candidate in wound healing. We also present a multifaceted in vitro model for the initial screening of new compounds that may be potentially useful in wound healing stimulation. Conclusion: The results show that peptide derived from PDGF-BB is a promising drug candidate for wound treatment.

Objective: Pediatric burns are a major source of injury and in the absence of adequate care can lead to lifelong functional loss and disfigurement. While split thickness skin autografts are the current standard of care for deep partial and full-thickness burns, this approach is associated with considerable morbidity. For this reason, alternative skin substitutes such as allografts have gained interest. Approach: In the present study, we present a case series of 30 children with various types of burns treated with dehydrated human amnion chorion membrane (dHACM). Results: We show that treatment with dHACM is associated with an excellent rate of healing comparable to split thickness skin grafts with less rate of hypertrophic scar and contracture. Innovation: Treatment with dHACM is particularly attractive as it consists of many tissue regenerative factors, such as growth factors and immune modulators, thus it will reduce the risk of scaring. Conclusion: While dHACM is associated with an increased upfront cost, treating patients with small to moderate-sized burns with dHACM in their regional centers works to decrease downstream costs such as management of prolonged pain from donor-site morbidity, revisional surgeries from scar and contractures of split thickness grafts, and avoiding the cost of transfer to higher level centers of care. Our findings challenge the current standard of care, suggesting that dHACM provides an alternative to the current use of split thickness skin grafting and is a safe, feasible, and potentially superior substitute for the management of small to moderate total body surface area partial and full-thickness pediatric burns.

Objective: Epidermal CD34(+) stem cells located in the hair follicle (HF) bulge area are capable of inducing HF neogenesis and enhancing wound healing after transplantation. In this study, we observed CD34(+) cells derived from blood directly participate in dermal regeneration during full-thickness excisional wound healing. Approach: We isolated and in vitro expanded a subset of hematopoietic stem cell (HSC)-like precursor cells from the peripheral blood of adult mice with the surface markers: CD34(+), leucine rich repeat containing G protein-coupled receptor 5 (LGR5)(+), CD44(+), c-kit(+), lineage negative (lin(−)), and E-cadherin(−). These blood-derived precursor cells (BDPCs), can be further differentiated into epithelial-like cells (eBDPCs) and secret fibroblast growth factor 9 (Fgf9) protein. Result: When transplanted into full-thickness skin wounds, eBDPC treatment produced accelerated healing and enhanced skin structure regeneration with less dermal scar formation. Also, HF neogenesis (HFN) was observed with incorporation of labeled BDPCs in the wound area. Innovation: Nondermal-derived CD34(+) cells (BDPCs) from the adult unmobilized peripheral blood are capable of in vitro expansion and differentiation. Successful establishment of an in vitro technical platform for BDPCs expansion and differentiation. The in vitro expanded and differentiated epithelial-like cells (eBDPCs) enhance wound healing and directly contribute to skin regeneration and HFN. Conclusion: BDPCs isolated and expanded from adult peripheral blood may provide a possible new cell-based treatment strategy for HF neogenesis and skin wound regeneration.

Objective: Skin graft donor site management is a concern particularly for elderly patients and patients with poor wound healing competence, and also because donor sites are a source of pain and discomfort. Although different types of dressings exist, there is no consensus regarding optimal dressing type on donor site care to promote healing, reduce pain, and improve patients' comfort. Approach: This prospective, single-center clinical trial evaluated the performance of nanofibrillar cellulose (NFC) wound dressing (FibDex (R) by UPM-Kymmene Corporation) for treatment of donor sites compared with a polylactide-based copolymer dressing. The study enrolled 24 patients requiring skin grafting with mean age of 49 +/- 18. The primary outcome measure was wound healing time. Secondary outcomes, the epithelialization, subjective pain, the scar appearance assessed using the Patient and Observer Scar Assessment Scale (POSAS), and skin elasticity and transepidermal water loss (TEWL), were evaluated at 1 and 6 months postoperatively. Results: No statistically significant differences were observed between NFC and copolymer dressings regarding wound healing time, epithelialization, experience of pain, or TEWL. Significant differences were observed in the POSAS results for thickness and vascularity in the Observer score, in the favor of NFC over copolymer dressing. Moreover, skin elasticity was significantly improved with NFC dressing in terms of viscoelasticity and elastic modulus at 1 month postoperatively. Innovation: NFC dressing is a new, green sustainable product for wound treatment without animal or human-origin components. Conclusion: NFC dressing provides efficient wound healing at skin graft donor sites and is comparable or even preferable compared with the copolymer dressing.

Objective: Severe pressure ulcers (PUs) do not respond to conservative wound therapy and need surgical repair. To better understand the pathogenesis and to advance on new therapeutic options, we focused on the proteomic analysis of PU, which offers substantial opportunities to identify significant changes in protein abundance during the course of PU formation in an unbiased manner. Approach: To better define the protein pattern of this pathology, we performed a proteomic approach in which we compare severe PU tissue from spinal cord injury (SCI) patients with control tissue from the same patients. Results: We found 76 proteins with difference in abundance. Of these, 10 proteins were verified as proteins that define the pathology: antithrombin-III, alpha-1-antitrypsin, kininogen-1, alpha-2-macroglobulin, fibronectin, apolipoprotein A-I, collagen alpha-1 (XII) chain, haptoglobin, apolipoprotein B-100, and complement factor B. Innovation: This is the first study to analyze differential abundance protein of PU tissue from SCI patients using high-throughput protein identification and quantification by tandem mass tags followed by liquid chromatography tandem mass spectrometry. Conclusion: Differential abundance proteins are mainly involved in tissue regeneration. These proteins might be considered as future therapeutic options to enhance the physiological response and permit cellular repair of damaged tissue. This work was supported by grants from the Instituto de Salud Carlos III (PI14/01917, PI18/00995, PT13/0001/0013) for Funding: ISCIII (‘‘PI14/01917, PI18/00995, PT13/0001/0013)’’, co-funded by ERDF/ESF, ‘‘Investing in your future’’. Redes Tema ticas de Investigacion Cooperativa (FONDOS FEDER, RD12/0042/0071). Sociedad Espanola de Cardiologıa para la Investigacion Basica 2017. Grant PRB3 (IPT17/0019—ISCIII-SGEFI/ERDF). These results are aligned with the Spanish initiative on the Human Proteome Project (SpHPP). Sí

Objective: To develop a venous leg ulcer (VLU) risk stratification system for use in research and clinical practice. Approach: U.S. Wound Registry data were examined retrospectively and assigned an outcome. Bivariate analysis identified significant variables (p

Objective: Venous leg ulcers (VLUs) comprise 80% of leg ulcers. One of the key parameters that can promote healing of VLUs is tissue oxygenation. To date, clinicians have employed visual inspection of the wound site to determine the healing progression of a wound. Clinicians measure the wound size and check for epithelialization. Imaging for tissue oxygenation changes surrounding the wounds can objectively complement the subjective visual inspection approach. Herein, a handheld noncontact near-infrared optical scanner (NIROS) was developed to measure tissue oxygenation of VLUs during weeks of treatment. Approach: Continuous-wave-based diffuse reflectance measurements were processed using Modified Beer-Lambert's law to obtain changes in tissue oxygenation (in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation). The tissue oxygenation contrast obtained between the wound and surrounding tissue was longitudinally mapped across weeks of treatment of four VLUs (healing and nonhealing cases). Results: It was observed that wound to background tissue oxygenation contrasts in healing wounds diminished and/or stabilized, whereas in the nonhealing wounds it did not. In addition, in a very slow-healing wound, wound to background tissue oxygenation contrasts fluctuated and did not converge. Innovation: Near-infrared imaging of wounds to assess healing or nonhealing of VLUs from tissue oxygenation changes using a noncontact, handheld, and low-cost imager has been demonstrated for the first time. Conclusion: The tissue oxygenation changes in wound with respect to the surrounding tissue can provide an objective subclinical physiological assessment of VLUs during their treatment, along with the gold-standard visual clinical assessment.

Objective: To fabricate and investigate the properties of fibroin and polyvinyl alcohol (PVA) hydrogels containing sericin prepared using high-pressure carbon dioxide (CO(2)). Approach: In this study, fibroin/PVA hydrogels with and without sericin were prepared using the high-pressure CO(2) method. The physical and mechanical properties of the hydrogels were investigated using field-emission scanning electron microscopy, Fourier-transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry, and the swelling, water retention, and compressive properties were assessed. Results: The hydrogels obtained from the combination of fibroin and PVA presented a compositional gradient along the hydrogel thickness and structure. The upper layer of the hydrogel consisted of a fibroin-based hydrogel blended with PVA, whereas the lower layer contained only fibroin. The mechanical properties regarding compression of the fibroin/PVA hydrogel were significantly better than those of the pure fibroin hydrogel, for hydrogels with and without sericin. Moreover, the mechanical properties of the hydrogels with sericin were significantly better than those without sericin. The water contents of all samples were >90%. Innovation: This study assessed a new combination of a wound healing agent and a biomaterial dressing. Moreover, this hydrogel production technique used a clean method without the need for a chemical crosslinking agent. Conclusion: The combination of the fibroin and PVA hydrogel and sericin prepared using the high-pressure CO(2) method led to good physical properties. This material may be a candidate for medical applications.

Objective: To prepare efficient antibacterial carvacrol (CAR) and thymol (THY)-loaded electrospun polycaprolactone (PCL)-based wound dressings. Approach: Using electrospinning we were able to prepare wound dressings with antimicrobial action thanks to their large surface per volume ratio, which allows their loading with therapeutic amounts of active principles. By nuclear magnetic resonance we demonstrated that the antimicrobial compounds are donors of hydrogen bonds to the ester functional group in PCL, which acts as acceptor and that intermolecular interaction is responsible for the high drug loading achieved. Results: Those mats loaded with CAR and THY without the use of solubilizing agents were able to completely eradicate both Gram-positive (Staphylococcus aureus ATCC 25923) and Gram-negative (Escherichia coli S17 strain) bacteria at doses inferior to the ones needed when using the free nonsupported compounds. A superior antimicrobial action was observed for THY and CAR against Gram-negative bacteria than against Gram-positive bacteria, despite the higher hydrophilicity of the outer layer of Gram-negative bacteria. Innovation: We demonstrate that a direct contact between the bacteria and the dressing is required to elicit antimicrobial action. We also evaluated drug loadings by gas chromatography coupled with mass spectrometry and nuclear magnetic resonance validating a new analytical approach. Finally we were able to visualize the pathogenic bacteria on the dressings by confocal microscopy. Conclusion: The interaction between the PCL-based mat and the pathogenic bacteria is a key issue to achieve complete pathogen eradication. Under no-contact conditions, released CAR or THY from the electrospun mats did not exert any antimicrobial action at the doses tested.

Objective: Relevant animal models to study effects of bacterial aggregates on wound healing are lacking. We aimed at establishing an equine wound model with bacterial aggregates to investigate the impact of bacterial inoculation on normal (thorax) and impaired (limb) wound healing. Approach: Wounds were created on three limbs and both thorax sides of six horses. Twelve out of 20 wounds per horse were inoculated with 104Staphylococcus aureus and 105Pseudomonas aeruginosa on day 4. Healing was monitored until day 27 by clinical assessment, including wound scoring, surface pH measurements, and digital photography for area determination. Biopsies were used for bacterial culture and for peptide nucleic acid fluorescence in situ hybridization to detect bacterial aggregates. Results: Inoculated limb wounds healed slower than noninoculated limb wounds from day 10 onward (p

Objective: To develop a cost-effective and clinically usable therapy to treat full-thickness skin injuries. We accomplished this by preparing a viscoelastic hydrogel using polyethylene glycol (PEG)-modified platelet-free plasma (PEGylated PFP) combined with human adipose-derived stem cells (ASCs). Approach: PEGylated PFP hydrogels were prepared by polymerizing the liquid mixture of PEG and PFP±ASCs and gelled either by adding calcium chloride (CaCl(2)) or thrombin. Rheological and in vitro studies were performed to assess viscoelasticity and the ability of hydrogels to direct ASCs toward a vasculogenic phenotype, respectively. Finally, a pilot study evaluated the efficacy of hydrogels±ASCs using an athymic rat full-thickness skin wound model. Results: Hydrogels prepared within the range of 11 to 27 mM for CaCl(2) or 5 to 12.5 U/mL for thrombin exhibited a storage modulus of ∼62 to 87 Pa and ∼47 to 92 Pa, respectively. The PEGylated PFP hydrogels directed ASCs to form network-like structures resembling vasculature, with a fourfold increase in perivascular specific genes that were confirmed by immunofluorescent staining. Hydrogels combined with ASCs exhibited an increase in blood vessel density when applied to excisional rat wounds compared with those treated with hydrogels (110.3 vs. 95.6 BV/mm(2); p

Objectives: The meta-analysis was performed to summarize the available evidence and determine the healing effectiveness of autologous platelet-rich gel (APG) on diabetic foot (DF) wounds. Approach: PubMed and The Cochrane Library and CNKI databases were searched to identify prior randomized controlled trials. Methodological qualities of included studies were assessed using Cochrane Handbook for Systematic Reviews of Intervention. Healing rate was considered the primary outcome; the secondary outcomes included healing time and adverse events. Results: Fifteen studies involving a total of 827 subjects were analyzed in the meta-analysis. Considering the primary outcome, the average healing rate in APG group was 85.8% and ranged from 68.4% to 100%. Relatively, the control group was 57.4% and ranged from 18.2% to 75.0%. Eligible studies were compared with a fixed effects model (I(2) = 0.0%, p = 0.496), indicating a higher healing rate with APG (risk ratio [RR] 1.44, 95% confidence interval [CI]: 1.32–1.57, z = 8.50, p

Background and Objective: Despite the effectiveness of skin autotransplantation, the high degree of immunogenicity of the skin precludes the use of allografts and systemic immunosuppression is generally inappropriate for isolated skin grafts. Indoleamine 2,3 dioxygenase (IDO) is a potent immunoregulatory factor with allo- and autoimmune suppression and tolerance induction properties. This study examines the potential use of locally expressed IDO to prolong the allogeneic skin graft take in a mouse model. Approach: Syngeneic-fibroblasts were transfected with noncompetent IDO viral vector and the level of Kynurenine (Kyn) in conditioned medium was measured as an index for IDO activity. Either 1 or 3 × 10(6) IDO-fibroblasts were introduced intra/hypo-dermally to the mouse skin. The expression, localization, and functionality of IDO were then evaluated. The cell-injected areas were harvested and grafted on the back of allogeneic mice. The graft survival, immune-cells infiltration, and interaction with dendritic cells were evaluated. Results: The results showed a significant improvement in allogeneic graft take injected with 1 × 106 IDO-fibroblasts (18.4 ± 3.3 days) compared with control (12.2 ± 1.9 days). This duration increased to 35.4 ± 4.7 days in grafts injected with 3 × 10(6) IDO-expressing cells. This observation might be due to a significantly lower T cells infiltration within the IDO-grafts. Further, the result of a flow cytometric analysis showed that the expression of PD-L1/PD-L2 on CD11c+/eFluor+ cells in the regional lymph nodes of injected skin areas was significantly higher in IDO groups compared with control. Conclusion: These data suggest that allogeneic skin graft survival outcome can be prolonged significantly by local overexpression of IDO without any systemic effect.

Objective: The use of porcine xenograft (PX) is widely spread in burn care. However, it may cause immunologic responses and other ethical and cultural considerations in different cultures. Therefore, there is a need for alternatives. The aim of this work is to test a novel biosynthetic cellulose dressing (Epiprotect®) on burn patients. Approach: Charts from 38 patients with superficial burns (SBs) (n = 18) or excised burns (n = 20) that got biosynthetic cellulose dressing instead of PX at a national burn center during 3 years were reviewed. Time to healing, length of stay, and wound infection were extracted from the medical records. Results: SBs hospitalization time was 11 days comparable to PXs reported by others. In the excised group, median duration of hospital stay was 35 days. Time to healing was 28 days. Seven wound infections were confirmed in the superficial group (39%) and 11 infections in the excised group (61%). Patients with superficial wounds reported pain relief on application. Innovation: A dressing (17 × 21 cm) consisting of biosynthetic cellulose replacing PX. Conclusion: Outcome of treatment of SBs or temporary coverage of excised deep burns with biosynthetic cellulose is comparable to treatment with PX. However, biosynthetic cellulose has benefits such as providing pain relief on application and ethical or cultural issues with the material is nonexistent.

[Objective] Wound healing is a complex process that involves the interaction between different cell types and bioactive factors. Impaired wound healing is characterized by a loss in synchronization of these interactions, resulting in nonhealing chronic wounds. Chronic wounds are a socioeconomic burden, one of the most prominent clinical manifestations of diabetes, however, they lack satisfactory treatment options. The objective of this study was to develop polymeric composites that deliver ions having wound healing properties and evaluate its performance using a pressure ulcer model in diabetic mice. [Approach] To develop a polymeric composite wound dressing containing ion-releasing nanoparticles for chronic wound healing. This composite was chemically and physically characterized and evaluated using a pressure ulcer wound model in diabetic (db/db) mice to explore their potential as novel wound dressing. [Results] This dressing exhibits a controlled ion release and a good in vitro bioactivity. The polymeric composite dressing treatment stimulates angiogenesis, collagen synthesis, granulation tissue formation, and accelerates wound closure of ischemic wounds created in diabetic mice. In addition, the performance of the newly designed composite is remarkably better than a commercially available dressing frequently used for the treatment of low-exuding chronic wounds. [Innovation] The developed nanoplatforms are cell- and growth factor free and control the host microenvironment resulting in enhanced wound healing. These nanoplatforms are available by cost-effective synthesis with a defined composition, offering an additional advantage in potential clinical application. [Conclusion] Based on the obtained results, these polymeric composites offer an optimum approach for chronic wound healing without adding cells or external biological factors., This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER) through the projects MAT2012-38793 and MAT2015-68906-R, the EuroNanoMed3 project nAngioDerm funded through the Spanish Ministry of Science and Innovation (ref. PCI2019-103648), the Spanish Ministry of Education, Culture, and Sports with the FPU grant (ref. AP-2012-5310), EIT Health (project EIT PoC-2016-SPAIN-03), La Caixa Banking Foundation through their CaixaImpulse Program and Caixaimpulse 2.0 Consolidate Program (Ref. LCF/TR/CN18/52210003).

Objective: The initial wound measurement and regular monitoring of diabetic foot ulcers (DFU) is critical to assess treatment response. There is no standardized, universally accepted, quick, reliable, and quantitative assessment method to characterize DFU. To address this need, a novel topographic imaging system has been developed. Our study aims at assessing the reliability and practicality of the WoundVue(®) camera technology in the assessment of DFU. Approach: The WoundVue system is a prototype device. It consists of two infrared cameras and an infrared projector, and it is able to produce a three-dimensional (3D) reconstruction of the wound structure. Fifty-seven diabetic foot wounds from patients seen in a multidisciplinary foot clinic were photographed from two different angles and distances by using the WoundVue camera. Wound area, volume, and maximum depth were measured for assessment of reliability. Thirty-one of these wounds also had area calculated by using the established Visitrak™ system, and a correlation between the area obtained by using both systems was assessed. Results: WoundVue images analysis showed excellent agreement for area (intraclass correlation coefficient [ICC]: 0.995), volume (ICC: 0.988), and maximum depth (ICC: 0.984). Good agreement was found for area measurement by using the WoundVue camera and Visitrak system (ICC: 0.842). The average percentage differences between measures obtained by using the WoundVue from different angles for assessment of different sizes and shapes of wounds were 2.9% (95% confidence interval [CI]: 0.3–5.4), 12.9% (95% CI: 9.6–35.7), and 6.2% (95% CI: 2.3–14.7) for area, maximum depth, and volume, respectively. Innovation: This is the first human trial evaluating this novel 3D wound measurement device. Conclusion: The WoundVue system is capable of recreating a 3D model of DFU and produces consistent data. Digital images are ideal for monitoring wounds over time, and the WoundVue camera has the potential to be a valuable adjunct in diabetic foot wound care.

Objective: Chronic wounds are long-term nonhealing wounds that are refractory to treatment. These wounds can present elevated protease levels, leading to rapid degradation of native and exogenously added growth factors. This work focused on developing a protease-resistant growth factor formulation for treatment of chronic wounds presented with high protease activity. Approach: This study developed protease-resistant growth factor formulations comprising elastin-like peptides (ELPs) fused with a known protease inhibitor peptide or growth factor. The ELP component of the fusion proteins allows assembly of heterogeneous nanoparticles (NPs) putting the inhibitor in close proximity to the growth factor to be protected. Results: We show successful preservation of growth factor activity in high human neutrophil elastase (HNE) environment and in human chronic wound fluid derived from patients. We further show that these NPs result in enhanced collagen remodeling and resolution of inflammation in a full thickness wound supplemented with HNE in genetically diabetic mice. Innovation: Development of heterogeneous NPs that put the protease inhibitor in close proximity of the growth factor. Moreover, the modular nature of the NPs allows for protection of multiple growth factors by the same inhibitor without changing the amino acid sequence of the growth factor. Conclusion: Our results indicate that the developed NPs hold tremendous promise in chronic wound healing therapy and may further help the translation of growth factor therapies to clinic. The customizable template for the NP design allows for multifaceted use across several fields in research and medicine.

Objective: Inserts are typically used in conjunction with pressure garment to improve the outcomes of hypertrophic scar (HS) treatment. However, the types of insert materials currently available have many limitations, thus hindering their therapeutic effect. An innovative insert material, the Smart Scar Care Pad (SSCP), was invented to maximize treatment outcomes through enhanced compression and occlusion. The study aimed to investigate the properties of the SSCP and its efficacy to serve as a suitable insert material for HS management. Approach: The physical properties and biocompatibility of SSCP were examined. A self-controlled clinical study of 45-day intervention using SSCP in comparison with Plastazote was conducted on 25 subjects with HS. Study outcomes included scar parameters measured both subjectively and objectively and patient feedback questionnaire. Results: The SSCP demonstrated equivalent and even superior performance when compared with commercial products in tests of biological safety and physical properties. Both arms demonstrated significant time effects on Vancouver Scar Scale total score (p = 0.000), melanin score (p = 0.042), pliability (p = 0.039), and hydration score (p = 0.013). Significant intervention and time interaction effect was found in the pliability (p = 0.048). From the feedback questionnaire, patients reported that SSCP was more conformable and there was less displacement during movement (p = 0.040) compared with conventional insert. Innovation: The SSCP is the first insert that combined the pressure enhancing effect of a traditional pressure insert and occlusion effect of silicone insert. Conclusion: The SSCP can serve as a safe and effective insert material in HS treatment, especially in improving HS pliability.

Three-dimensional (3D) wound measurements enable the evaluation of wound healing from the wound bed, which may be a more sensitive measure than traditional two-dimensional (2D) area measurements at the level of the skin surface. Few studies have investigated 3D measurements for monitoring wound healing over time. The aim of this study was to compare the changes in 3D area measurements with traditional (2D) area measurements of diabetic foot ulcers during 8 weeks. Approach: In a prospective cohort study, we monitored the wound healing of 150 diabetic foot ulcers using the 3D-wound assessment monitor camera (3D area) and the digital imaging method (2D area) at baseline, weeks 2, 4, and 8. The following statistical approaches were used to compare the changes in 2D area and 3D area measurements: linear regression analysis, paired Wilcoxon rank test, Bonett-Price 95% confidence interval, and Spearman's correlation coefficient. Results: The overall changes in 3D area were significantly larger compared with 2D area as assessed by Wilcoxon test (p < 0.0001) and Bonett-Price 95% confidence interval of 0.009-0.163. In addition, comparison of 2D area and 3D area measurements showed that the majority of the wounds had larger decrease in 3D area compared with 2D area over time. Innovation: 3D area appears to provide a more sensitive method to monitor wound healing. Conclusion: Our study highlights the potential benefit of a novel 3D camera for monitoring wound healing of diabetic foot ulcers, which was found particularly useful in monitoring wound healing in large wounds. However, in small wounds (

Objective: Chronic wounds represent a highly prevalent but little recognized condition with substantial implications for patients and payers. While better wound care products and treatment modalities are known to improve healing rates, they are inconsistently used in real-world practice. Predicting healing rates of chronic wounds and comparing to actual rates could be used to detect and reward better quality of care. We developed a prediction model for chronic wound healing. Approach: We analyzed electronic medical records (EMRs) for 620,356 chronic wounds of various etiologies in 261,398 patients from 532 wound care clinics in the United States. Patient-level and wound-level parameters influencing wound healing were identified from prior research and clinician input. Logistic regression and classification tree models to predict the probability of wound healing within 12 weeks were developed using a random sample of 70% of the wounds and validated in the remaining data. Results: A total of 365,659 (58.9%) wounds were healed by week 12. The logistic and classification tree models predicted healing with an area under the curve of 0.712 and 0.717, respectively. Wound-level characteristics, such as location, area, depth, and etiology, were more powerful predictors than patient demographics and comorbidities. Innovation: The probability of wound healing can be predicted with reasonable accuracy in real-world data from EMRs. Conclusion: The resulting severity adjustment model can become the basis for applications like quality measure development, research into clinical practice and performance-based payment.

Objective: In recent years, reticulated open-cell foam-based closed-incision negative pressure therapy (ROCF-ciNPT) has shown effectiveness in management of various postoperative incisions. These dressings consist of a skin interface layer that absorbs fluid from the skin surface and reduces the potential for microbial colonization within the dressing by means of ionic silver. This study examines the ability of silver to reduce the bioburden within the dressing as well as the localized effect due to potential silver mobility. Approach: Ability of silver to reduce bioburden within the ROCF-ciNPT dressing was assessed using Staphylococcus aureus, Pseudomonas aeruginosa, and Candida spp. Furthermore, silver mobility was assessed using an in vitro skin model to study the zone of inhibition along with released silver quantification. Using a porcine model, diffusion of silver into blood and tissue was studied using emission spectrometry and histology. Results: Microbial growth in the ROCF-ciNPT dressing was significantly reduced (∼2.7–4.9 log reduction) compared to a silver-free negative control. No zone of inhibition was observed for microbial colonies for up to 7 days with minimal localized silver release (

Objective: The goal of any topical formulation is efficient transdermal delivery of its active components. However, delivery of compounds can be problematic with penetration through tough layers of fibrotic dermal scar tissue. Approach: We propose a new approach combining high-performance liquid chromatography (HPLC) and Raman spectroscopy (RS) using a topical of unknown composition against a well-known antiscar topical (as control). Results: Positive detection of compounds within the treatment topical using both techniques was validated with mass spectrometry. RS detected conformational structural changes; the 1,655/1,446 cm(−1) ratio estimating collagen content significantly decreased (p

Background and Objective: Impaired dermal wound healing represents a major medical issue in today's aging populations. Granulation tissue formation in the dermis and reepithelization of the epidermis are both important and necessary for proper wound healing. Although a number of artificial dermal grafts have been used to treat full-thickness dermal loss in humans, they do not induce reepithelization of the wound, requiring subsequent epithelial transplantation. In the present study, we sought a novel biomaterial that accelerates the wound healing process. Approach: We prepared a composite biomaterial made of jellyfish and porcine collagens and developed a hybrid-type dermal graft that composed of the upper layer film and the lower layer sponge made of this composite biomaterial. Its effect on dermal wound healing was examined using a full-thickness excisional wound model. Structural properties of the dermal graft and histological features of the regenerating skin tissue were characterized by electron microscopic observation and immunohistological examination, respectively. Results: The composite biomaterial film stimulated migration of keratinocytes, leading to prompt reepithelization. The regenerating epithelium consisted of two distinct cell populations: keratin 5-positive basal keratinocytes and more differentiated cells expressing tight junction proteins such as claudin-1 and occludin. At the same time, the sponge made of the composite biomaterial possessed a significantly enlarged intrinsic space and enhanced infiltration of inflammatory cells and fibroblasts, accelerating granulation tissue formation. Innovation: This newly developed composite biomaterial may serve as a dermal graft that accelerates wound healing in various pathological conditions. Conclusion: We have developed a novel dermal graft composed of jellyfish and porcine collagens that remarkably accelerates the wound healing process.

Objective: While myriads of studies have suggested that a survey of wound pH environment could indicate wound healing activities, it is not clear whether wound alkalinity can be used as a prognostic indicator of nonhealing wounds. Currently available systems cannot reliably assess the pH environment across wounds, which is the objective of this study. Approach: A disposable device, DETEC® pH, was developed and characterized on its ability to map wound alkalinity by pressing a freshly recovered wound dressing against its test surface. By comparing the wound's alkalinity and size reduction rates (∼7 days) following pH measurement, we assessed the capability of wound alkalinity to prognosticate subsequent short-term wound size reduction rates. Results: The device had high accuracy and specificity in determining the alkalinity of simulated wound fluids soaked onto wound dressing. The type of wound dressing type had an insignificant effect on its detection sensitivity. Upon testing discarded wound dressings from human patients, the device quickly determined alkaline and acidic wounds. Finally, statistical analyses of wound size reduction rates in wounds with various alkalinities confirmed that wound alkalinity has a strong influence on, at least, short-term wound healing activity. Innovation: Without directly contacting the patient, this device provides a quick assessment of wound alkalinity to prognosticate immediate and short-term wound healing activities. Conclusion: DETEC® pH may serve as a prognosis device for wound care specialists during routine wound assessment to predict wound healing progress. This information can assist the decision-making process in a clinical setting and augur well for chronic wound treatment. DETEC® pH can also be used as an aid for home health care nurses or health care providers to screen nonhealing wounds outside clinics.

Objective: To compare the tolerability and mechanical tensile strength of acute skin wounds closed with nylon suture plus a novel suture bridge device (SBD) with acute skin wounds closed with nylon suture in a porcine model. Approach: Four Yucatan pigs each received 12 4.5 cm full-thickness incisions that were closed with 1 of 4 options: Suture bridge with nylon, suture bridge with nylon and subdermal polyglactin, nylon simple interrupted, and nylon simple interrupted with subdermal polyglactin. Epithelial reaction, inflammation, and scarring were examined histologically at days 10 and 42. Wound strength was examined mechanically at days 10 and 42 on ex vivo wounds from euthanized pigs. Results: Histopathology in the suture entry/exit planes showed greater dermal inflammation with a simple interrupted nylon suture retained for 42 days compared with the SBD retained for 42 days (p