Potential Application of Modified mRNA in Cardiac Regeneration.

Heart failure remains the leading cause of human death worldwide. After a heart attack, the formation of scar tissue due to the massive death of cardiomyocytes leads to heart failure and sudden death in most cases. In addition, the regenerative ability of the adult heart is limited after injury, partly due to cell-cycle arrest in cardiomyocytes. In the current post-COVID-19 era, urgently authorized modified mRNA (modRNA) vaccines have been widely used to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, modRNA-based protein replacement may act as an alternative strategy for improving heart disease. It is a safe, effective, transient, low-immunogenic, and integration-free strategy for in vivo protein expression, in addition to recombinant protein and stem-cell regenerative therapies. In this review, we provide a summary of various cardiac factors that have been utilized with the modRNA method to enhance cardiovascular regeneration, cardiomyocyte proliferation, fibrosis inhibition, and apoptosis inhibition. We further discuss other cardiac factors, modRNA delivery methods, and injection methods using the modRNA approach to explore their application potential in heart disease. Factors for promoting cardiomyocyte proliferation such as a cocktail of three genes comprising FoxM1, Id1, and Jnk3-shRNA (FIJs), gp130, and melatonin have potential to be applied in the modRNA approach. We also discuss the current challenges with respect to modRNA-based cardiac regenerative medicine that need to be overcome to apply this approach to heart disease. This review provides a short description for investigators interested in the development of alternative cardiac regenerative medicines using the modRNA platform.

Risk factors for postoperative adverse airway events in patients with primary oral cancer undergoing reconstruction without prophylactic tracheostomy.

OBJECTIVE: To identify risk factors associated with adverse airway events (AAEs) in primary oral cancer patients undergoing tumor ablation followed by free tissue transfer without prophylactic tracheostomy. METHODS: We retrospectively collected primary oral cancer patients who underwent tumor ablation surgery following free-tissue transfer without prophylactic tracheostomy during February 2017 to June 2019 in Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan. 379 patients were included. Data were analysed from 2020 to 2021. Demographics, comorbidities, intraoperative variables and postoperative respiration profile were obtained from the medical record. Main outcome was postoperative AAEs, including requirement of endotracheal intubation after extubation and tracheostomy after prolonged intubation. RESULTS: Of the 379 patients, postoperative AAEs happened in 29 patients (7.6 %). In reintubation group, patients were older with more diabetes mellitus, hypertension and cerebrovascular disease. These patients had lower preoperative hemoglobin, creatinine, and albumin level with more intraoperative blood transfusion. In postoperative respiration profile, rapid shallow breathing index (RSBI) and PaO2/FiO2 (PF) ratio were poorer. On multivariate analysis, patient's age, tumor location, and cross-midline segmental mandibulectomy and a lower PF ratio were independent risk factors for postoperative AAEs. CONCLUSIONS: In head and neck cancer patients that underwent tumor ablation followed by free tissue transfer without prophylactic tracheostomy, patient's age, tumor location, cross-midline segmental mandibulectomy and P/F ratio are associated with postoperative AAEs.

Sustained Release of Tacrolimus Embedded in a Mixed Thermosensitive Hydrogel for Improving Functional Recovery of Injured Peripheral Nerves in Extremities.

Vascularized composite allotransplantation is an emerging strategy for the reconstruction of unique defects such as amputated limbs that cannot be repaired with autologous tissues. In order to ensure the function of transplanted limbs, the functional recovery of the anastomosed peripheral nerves must be confirmed. The immunosuppressive drug, tacrolimus, has been reported to promote nerve recovery in animal models. However, its repeated dosing comes with risks of systemic malignancies and opportunistic infections. Therefore, drug delivery approaches for locally sustained release can be designed to overcome this issue and reduce systemic complications. We developed a mixed thermosensitive hydrogel (poloxamer (PLX)-poly(l-alanine-lysine with Pluronic F-127) for the time-dependent sustained release of tacrolimus in our previous study. In this study, we demonstrated that the hydrogel drug degraded in a sustained manner and locally released tacrolimus in mice over one month without affecting the systemic immunity. The hydrogel drug significantly improved the functional recovery of injured sciatic nerves as assessed using five-toe spread and video gait analysis. Neuroregeneration was validated in hydrogel-drug-treated mice using axonal analysis. The hydrogel drug did not cause adverse effects in the mouse model during long-term follow-up. The local injection of encapsulated-tacrolimus mixed thermosensitive hydrogel accelerated peripheral nerve recovery without systemic adverse effects.

Homodigital Pedicled Digital Artery Perforator flaps for fingertip reconstruction - a review of flap options.

Background: Digital artery perforator flaps provide a useful option for reconstruction of soft tissue defects of the digits, and many variations of these flaps have been described for fingertip defects. This review aims to summarize various pedicled digital artery perforator flap anatomical configurations described in literature for fingertip reconstruction and their results. Methods: A literature review of PubMed, Medline and Embase databases was conducted. Studies reporting homodigital digital artery perforator flaps for fingertip reconstruction without sacrificing the proper digital artery were included in the review. Data collected included flap design, perforator location, pathology, defect location, flap dimensions, flap survival, sensory recovery, range of movement, outcome measures, and complications. The flaps were analysed and categorized based on flap location, flap design, transfer method, and flap innervation. Results: Pedicled digital artery perforators have been described in various configurations by different authors including propeller, bilobed, V-Y advancement, rotation and turnover flaps. Variations to make these flaps sensate have also been described. According to the available reports, these flaps have low complications and high patient satisfaction rates. Conclusion: Pedicled digital artery perforator flaps provide a versatile option for the reconstruction of fingertip and thumb tip defects. Various flap options are available for use depending on the reconstructive need. They are quicker and easier to perform than free flaps and can provide excellent outcomes in suitable cases.

The impact of depression on survival of head and neck cancer patients: A population-based cohort study.

Background: Depression is common among patients with head and neck cancer, thereby affecting their survival rate. However, whether close monitoring of depression affects the survival outcomes of these patients is unknown. Therefore, this study aimed to determine whether depression treatment continuity after the diagnosis of cancer affects the survival of these patients. Methods: A total of 55,069 patients diagnosed with head and neck cancer in the Cancer Registration System database in Taiwan were enrolled. This cohort was followed from January 1, 2007 to December 31, 2017. Furthermore, the patients were divided into four groups, namely, "no depression," "pre-cancer only," "post-cancer only," and "both before and after cancer," on the basis of the diagnosis of depression and the duration of the follow-up period in the psychiatric clinic. Further, the Cox proportional hazard model was applied to estimate the hazard of death for the four groups. Results: A total of 6,345 (11.52%) patients were diagnosed with depression in this cohort. The "pre-cancer only" group had a lower overall survival (HR = 1.18; 95% CI = 1.11-1.25) compared with the "no depression" group. Moreover, the "post-cancer only" group had better overall survival (HR = 0.88; 95% CI = 0.83-0.94) compared with the "no depression" group, especially in advanced-stage patients. Patients who were diagnosed with depression before cancer and had continuous depression treatments after the cancer diagnosis had better overall survival (HR = 0.78; 95% CI = 0.71-0.86) compared with patients who had treatment interruptions. Conclusion: Patients with pre-cancer depression had poorer survival outcomes, especially those who did not receive psychiatric clinic visits after their cancer diagnosis. Nonetheless, in patients with advanced-stage cancer, depression treatment may improve overall survival.

Does Inclination of the Toe Proximal Phalangeal Head Affect the Outcomes of Vascularized Joint Transfers? Retrospective Study of 22 Joint Transfers.

BACKGROUND: Different shapes of the proximal phalangeal head of toe proximal interphalangeal joints (e.g., oval and circular) are observed in vascularized joint transfers. The difference in shape implies the varying degrees of inclination of the articular surfaces between toes. This study investigated the impact of articular inclination on outcomes after toe joint transfers for finger proximal interphalangeal joint reconstruction. METHODS: Twenty-one patients who underwent vascularized joint transfer from May of 2009 to May of 2018 were included. Their mean age was 33.4 years and mean follow-up period was 28.9 months. All patients had a type I central slip according to the Te classification. Articular surface inclination was measured on lateral radiographic views. RESULTS: Passive range of motion of the toe proximal interphalangeal joint before vascularized joint transfer was 71.1 ± 9.6 degrees. The functional range of motion of the reconstructed proximal interphalangeal joint was 60.0 ± 17.0 degrees. The extensor lag after the joint transfer was 9.4 ± 19.6 degrees. The articular inclination of the toe joint was 71.9 ± 9.7 degrees. A Pearson correlation analysis of all variables, including age, preoperative range of motion of the toe joint, postoperative range of motion of the reconstructed joint, articular inclination of the toe joint, and extensor lag of the reconstructed joint with toe articular inclination, was performed. There was no significant correlation between articular inclination of the toe joint and extensor lag of the reconstructed joint ( p = 0.226). CONCLUSION: The articular surface inclination of the toe did not affect the functional range of motion after joint transfer. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice.

(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-ß1 and activate the TGF-ß/Smad3 signaling pathway. Fibroblasts activated by TGF-ß1containing exosomes from ASCs initiate the production of TGF-ß1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-ß1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.

The Effect on Venous Congestion of Diverting Arterial Flow in the Arterialized Venous Flap.

An arterialized venous flap is a cutaneous flap based solely on subcutaneous veins. The flap is perfused by nonphysiologic flow of blood from the vein into the peripheral tissue. This nonphysiologic perfusion limits the indications for an arterialized venous flap, and its postoperative complications make it an unpopular choice for reconstruction. When venous flaps are designed following the direction of venous valves (antegrade) in a flow-through fashion, the blood may bypass the peripheral tissue without perfusing the flap. A higher pressure within the efferent end of the vein impedes venous return from the peripheral tissue into this draining vein. Thus, venous congestion of the arterialized venous flap becomes inevitable. We describe our approach to designing an arterialized venous flap in which direct arteriovenous shunting is largely eliminated, thereby transmitting a higher pressure in the periphery of the flap while maintaining a physiologic venous pressure in the efferent vein. This restriction of shunting can be accomplished in a number of ways, depending on the venous pattern within the flap.

Reverse Superficial Palmar branch of Radial artery pedicled flap for Palmar and Digital reconstruction: A systematic review of literature with a retrospective case review.

BACKGROUND: Most studies on the superficial palmar branch of radial artery (SUPBRA) flap involve its use as a free flap with only few reports in literature regarding its use as a reverse pedicled flap. This systematic review presents a summary of the available literature on the indications, anatomy, technique, complications and outcomes of the reverse SUPBRA flap and also describes our experience. METHODS: A computer search was performed on the Embase, Medline and Pubmed databases for clinical studies describing the reverse SUPBRA flap in accordance with the standard principles for systematic review and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A retrospective review of cases performed by the senior author was also conducted. RESULTS: Seven studies qualified for the review with 50 flaps in 50 patients meeting the inclusion criteria. The senior author has performed nine reverse SUPBRA flaps from 2006 to 2015. The flap was found to be most useful for defects of the thumb, index, palm and first webspace. Variations in vascular anatomy may necessitate a change of operative strategy. Venous congestion was common but transient in the majority. Complications were rare and included minor tip necrosis, scar contracture, donor site sensitivity and numbness, thumb adduction contracture and cold intolerance. CONCLUSIONS: The reverse SUPBRA flap is a versatile flap for reconstructing defects of the thumb, index, palm and first webspace. It is quick to raise, has a low donor site morbidity and complication rate and achieves very reasonable functional and aesthetic outcomes.

National Population Study of the Effect of Structure and Process on Outcomes of Digit Replantation.

BACKGROUND: Surgeon experience, hospital volume, and teaching hospital status may play a role in the success of digit replantation. This study aims to analyze factors that influence digit replantation success rates. STUDY DESIGN: We examined patients with traumatic digit amputations, between 2000 and 2015, from the National Health Insurance Research Database (NHIRD) of Taiwan, which comprises data of more than 99% of its population. We measured the number of traumatic digit amputations and success rate of replantation. Chi-square and ANOVA tests were used for descriptive statistics. Regression models were built to analyze the association among patient, surgeon, and hospital characteristics, and replant success. RESULTS: We identified 13,416 digit replantation patients using the eligibility criteria. The overall replantation failure rate was significantly higher in medium- and high-volume hospitals (low-volume: 11%, medium-volume: 17%, and high-volume: 15%, p < 0.001). Teaching hospitals had significantly higher replantation failure rates [(15.5% vs 7.6%), odds ratio (OR) 2.0; confidence interval (CI) 1.1-3.7]. Lower surgeon case volume resulted in a significantly higher failure rate in the thumb replantation (OR 0.89; CI 0.85-0.94). CONCLUSIONS: Teaching hospitals had greater odds of replantation failure, owing to being high volume centers and attempting more replantations. However, the effect of residents performing the replantation during their training should be considered. Teaching units are mandatory for resident training; however, a balance should be established to provide training, but with sufficient supervision to achieve optimal replant success. A national protocol to triage digit amputation cases to high volume centers with experienced microsurgeons will help improve the replantation success rate.

The Anterolateral Thigh Perforator Flap: Its Expanding Role in Lower Extremity Reconstruction.

The anterolateral thigh (ALT) flap is a popular flap for lower extremity reconstruction despite its varied pedicle anatomy. Beyond its use for soft tissue coverage, using the chimeric flap concept, the ALT flap is useful for tendon and ligament reconstruction and the creation of a gliding surface with the fascia lata component. The vastus lateralis muscle can be included for dead-space obliteration. The main pedicle is long and is a similar size match for major artery reconstruction. If several perforators are available, a split flap could be fashioned into a multitude of shapes all arising from the same pedicle.

Trunkoplasty after massive weight loss - a case series with a one-stage body contouring procedure for the NHS patient.

Body contouring post massive weight loss (MWL) is a considerable task and is often a functional rather than esthetic operation. Clinicians are often encouraged to solve multiple issues in a single setting that can be difficult in the MWL patient. A simple abdominoplasty often does not provide a satisfactory outcome in such patients and may result in disharmony of the esthetic unit of the trunk. Trunkoplasty is a technique that combines a fleur-de-lis abdominoplasty and reverse abdominoplasty. This is a one-stage operation to address the extra skin of the whole trunk esthetic unit. The average operation time was 4 h with a 3-surgeon team. No blood transfusions were required. There were 3 out of 15 patients with wound-related problems and no incidence of postoperative hematomas. There were no returns to theaters. Seromas formed were not symptomatic and no interventions were required. The average inpatient stay was 6.9 days and a return to work after 4 weeks. It can improve abdominal contour, define the waist, and improve mons ptosis in one stage without any change in position. This procedure has some specific advantages (accommodates preexisting abdominal scars), but also has shortcomings as compared to "standard" circumferential body contouring.

A Reversed Inset Toe PIPJ Vascularized Joint Transfer for Finger PIPJ Composite Defect Reconstruction.

Free vascularized joint transfers (VJT) are indicated for reconstruction of a composite defect of the finger joints. When the bone defect involves the proximal interphalangeal joint (PIPJ) and the full length of the middle phalanx, using the toe PIPJ with a shorter middle phalanx to reconstruct such a defect will be difficult. In this article, we describe an unusual application to repair the composite defect with a reversed inset of the toe PIPJ, where the proximal phalanx of the toe is placed distally and vice versa. METHODS: We describe a new technique to repair the composite defect with a reversed inset of the toe PIPJ. A 33-year-old woman sustained a crush injury to the left, middle, and ring finger, having fallen off her moped in a road traffic incident. A vascularized PIPJ from the second toe along with a hemipulp (1 × 4 cm) from the great toe transfer was performed with a reverse inset. RESULTS: With intensive physiotherapy and surgical tenolysis, a range of motion of 20-80 degrees at the new PIPJ was achievable. The joint motion was stable, and the radiograms of the finger demonstrated no visible joint degeneration. She reported the use of the finger, which improved overall hand function. CONCLUSION: Reverse inset of toe PIPJs is possible in simultaneous reconstruction of damaged finger PIPJs and building up of bony length distally.

Dorsal Metatarsal Artery Perforator (DMtAP) flap Reconstruction of the Foot - A Review.

The dorsal metatarsal artery perforator (DMtAP) flap is a relatively new flap in the reconstructive armamentarium. Our understanding has only recently increased with data from cadaveric dissections, which have increased our understanding of the DMtAP system of the forefoot. Sporadic reports in the literature have been published regarding its various uses for defects around the forefoot. This review aims to summarize the reports and results thus far in the literature and bring together the anatomical evidence of DMtAPs in the forefoot. We also demonstrate our experience in raising a DMtAP flap and its potential use for reconstruction of the forefoot after skin cancer surgery. This is a versatile and reliable flap.

Human Wharton's Jelly Mesenchymal Stem Cell-Mediated Sciatic Nerve Recovery Is Associated with the Upregulation of Regulatory T Cells.

The acceleration of peripheral nerve regeneration is crucial for functional nerve recovery. Our previous study demonstrated that human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSC) promote sciatic nerve recovery and regeneration via the direct upregulation and release of neurotrophic factors. However, the immunomodulatory role of hWJ-MSC in sciatic nerve recovery remains unclear. The effects of hWJ-MSC on innate immunity, represented by macrophages, natural killer cells, and dendritic cells, as well as on adaptive immunity, represented by CD4+ T, CD8+ T, B, and regulatory T cells (Tregs), were examined using flow cytometry. Interestingly, a significantly increased level of Tregs was detected in blood, lymph nodes (LNs), and nerve-infiltrating cells on POD7, 15, 21, and 35. Anti-inflammatory cytokines, such as IL-4 and IL-10, were significantly upregulated in the LNs and nerves of hWJ-MSC-treated mice. Treg depletion neutralized the improved effects of hWJ-MSC on sciatic nerve recovery. In contrast, Treg administration promoted the functional recovery of five-toe spread and gait stance. hWJ-MSC also expressed high levels of the anti-inflammatory cytokines TGF-ß and IL-35. This study indicated that hWJ-MSC induce Treg development to modulate the balance between pro- and anti-inflammation at the injured sciatic nerve by secreting higher levels of anti-inflammatory cytokines.

The impact of hospital, surgeon, and patient characteristics on digit replantation decision: A national population study.

BACKGROUND: Traumatic finger amputations cause a substantial burden to health care system. The purpose of this study is to investigate the epidemiology of traumatic finger amputations, the incidence of replantation attempts and to examine the patient, surgeon, and hospital characteristics that were associated with replantation attempts. METHODS: We examined 49,469 patients with traumatic digit amputations from the National Health Insurance Research Database (NHIRD) of Taiwan. We used Chi-square, ANOVA tests, and regression analysis to determine the important factors in decision to replant. RESULTS: The replantation rate increased significantly with increased hospital volume (low-volume: 4.7%, medium-volume: 19.1 % and high-volume: 35.9 %). Regional hospitals were more likely to attempt replantation (odds ratio = 1.35). Low-volume hospitals had a replantation failure rate of 11.1 %, medium-volume 19.7 % and high-volume hospitals had 13.8 %. CONCLUSION: With the national health insurance coverage, hospital volume is a substantial factor to encourage microsurgical-trained staff to perform digit replantation when indicated. The findings from this study will support government initiatives to foster and reward regionalization centers with high to medium case volume of replants to manage this critical function restoring procedure.

Perforator Dissection Simulation: A High-Fidelity Five-Flap Porcine Training Model.

INTRODUCTION: Perforator dissection can be technically demanding with a steep learning curve. Inadvertent perforator damage during dissection can be minimized with practice and familiarity with tissue-handling techniques unique to perforator dissection. There currently lacks a simulation model that mimics the human perforator in size and course. We present a porcine training model with five consistent perforator flaps per side that can be readily harvested and is a reproducible simulation model. MATERIALS AND METHODS: Five fresh cadaveric pigs were used in this study to evaluate the feasibility and location of the perforators. Ten perforators were dissected out in each pig (five per side) by the same surgeon. The length of perforator was measured and intramuscular route was noted. The ease of dissection was graded, and its similarity to actual surgery was graded as well. RESULTS: Five consistent perforators were identified across each side of five fresh cadaveric pigs. The perforators were located, namely in the neck, anterior flank, posterior flank, rectus and hindlimb. They were fasciocutaneous and had an intramuscular course of each (average 2.5 cm length). The perforators were found to be on each side of the pig, giving ten perforators for dissection practice in total. DISCUSSION: The five perforators named in this porcine model are easily replicated and can be performed for perforator dissection simulation and practice.