Demographic and physiological factors associated with clinically significant eyelid edema in patients following upper eyelid surgery.

PURPOSE: To investigate demographic and physiological variables associated with clinically significant edema after upper eyelid surgery. METHODS: A retrospective chart review was performed on patients who underwent blepharoplasty or external levator advancement with or without lid crease formation between January 2018 and January 2021 at the University of Southern California. Age, sex, pertinent medical history (medications causing edema and comorbidities), and pertinent surgical procedures were all collected. Postoperative photos were graded by two independent physician graders on a newly developed photographic scale ranging from 0 (no edema) to 3 (severe edema). Clinically significant edema of the eyelids was defined as Grade 3 edema at any postoperative point or ≥ Grade 1 edema after 90 days post operation. Patients without postoperative photos were excluded. Mann-Whitney U test, Fisher's exact test, and χ2 test were used to compare groups with and without significant edema. All analyses were conducted using SAS version 9.4 (SAS Institute Inc.) with α=0.05. RESULTS: Out of 217 patients, East Asian participants had higher odds of developing edema than White participants (odds ratio, 7.92; CI, 3.15-19.93, p < 0.0001) and Hispanic participants (odds ratio, 3.47; CI, 1.51-7.97, p = 0.003). Southeast Asian participants also had higher odds of developing CSEE than White participants (odds ratio, 6.19; CI, 1.71-22.43, p = 0.006). Fifty-four (24.9%) patients had clinically significant edema. Although BMI, medical comorbidities, medication use, and age did not affect edema, there was a statistically significant relationship between race and incidence of edema (p = 0.0001). Those in the CSEE group were also more likely to require reoperation (p = 0.0143). CONCLUSIONS: There is a statistically significant relationship between Asian race and the incidence of clinically significant eyelid edema. CSEE is associated with a higher incidence of reoperation.

Tissue Expanders in Staged Calvarial Reconstruction: A Systematic Review.

Cranioplasties are common procedures in plastic surgery. The use of tissue expansion (TE) in staged cranioplasties is less common. We present two cases of cranioplasties with TE and systematically review literature describing the use of TE in staged cranioplasties and postoperative outcomes. A systematic review was performed by querying multiple databases. Eligible articles include published case series, retrospective reviews, and systematic reviews that described use of TE for staged bony cranioplasty. Data regarding study size, patient demographics, preoperative characteristics, staged procedure characteristics, and postoperative outcomes were collected. Of 755 identified publications, 26 met inclusion criteria. 85 patients underwent a staged cranioplasty with TE. Average defect size was 122 cm 2 , and 30.9% of patients received a previous reconstruction. Average expansion period was 14.2 weeks. The most common soft tissue closures were performed with skin expansion only (75.3%), free/pedicled flap (20.1%), and skin graft (4.7%). The mean postoperative follow-up time was 23.9 months. Overall infection and local complication rates were 3.53 and 9.41%, respectively. The most common complications were cerebrospinal fluid leak (7.1%), hematoma (7.1%), implant exposure (3.5%), and infection (3.5%). Factors associated with higher complication rates include the following: use of alloplastic calvarial implants and defects of congenital etiology ( p = 0.023 and 0.035, respectively). This is the first comprehensive review to describe current practices and outcomes in staged cranioplasty with TE. Adequate soft tissue coverage contributes to successful cranioplasties and TE can play a safe and effective role in selected cases.

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Prolymphangiogenic Effects of 9-cis Retinoic Acid Are Enhanced at Sites of Lymphatic Injury and Dependent on Treatment Duration in Experimental Postsurgical Lymphedema.

Background: Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9-cis retinoic acid (9-cis RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Methods and Results: Short-duration treatment with 9-cis RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9-cis RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Conclusions: Given the reported results indicating that 9-cis RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9-cis RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.

Urinary Bladder Matrix Improves Irradiated Wound Healing in a Murine Model.

ABSTRACT: Radiation skin damage is associated with chronic wounds and poor healing. Existing localized treatment modalities have limited benefit. Therefore, there has been increased interest in biologically based solutions. In this study, we aimed to determine the effect of topical urinary bladder matrix (UBM) on chronic irradiated skin wounds using an established murine model. Our findings demonstrated that topical urinary bladder matrix significantly accelerated the healing of irradiated wounds on day 7 (P = 0.0216), day 14 (P = 0.0140), and day 21 (P = 0.0393). Histologically, urinary bladder matrix treatment was associated with higher-quality reorganization and reepithelialization of wounds, an increased density of myofibroblasts (P = 0.0004), and increased collagen deposition (P < 0.0001). In addition, quantitative real-time polymerase chain reaction data demonstrated decreased expression of profibrotic mediators (P = 0.0049). We conclude that urinary bladder matrix may be a useful, noninvasive, adjunctive therapy for the treatment of chronic irradiated skin wounds.

Current Understanding of Pathological Mechanisms of Lymphedema.

Significance: Lymphedema is a common disease that affects hundreds of millions of people worldwide with significant financial and social burdens. Despite increasing prevalence and associated morbidities, the mainstay treatment of lymphedema is largely palliative without an effective cure due to incomplete understanding of the disease. Recent Advances: Recent studies have described key histological and pathological processes that contribute to the progression of lymphedema, including lymphatic stasis, inflammation, adipose tissue deposition, and fibrosis. This review aims to highlight cellular and molecular mechanisms involved in each of these pathological processes. Critical Issues: Despite recent advances in the understanding of the pathophysiology of lymphedema, cellular and molecular mechanisms underlying the disease remains elusive due to its complex nature. Future Directions: Additional research is needed to gain a better insight into the cellular and molecular mechanisms underlying the pathophysiology of lymphedema, which will guide the development of therapeutic strategies that target specific pathology of the disease.

Current Advancements in Animal Models of Postsurgical Lymphedema: A Systematic Review.

Significance: Secondary lymphedema is a debilitating disease caused by lymphatic dysfunction characterized by chronic swelling, dysregulated inflammation, disfigurement, and compromised wound healing. Since there is no effective cure, animal model systems that support basic science research into the mechanisms of secondary lymphedema are critical to advancing the field. Recent Advances: Over the last decade, lymphatic research has led to the improvement of existing animal lymphedema models and the establishment of new models. Although an ideal model does not exist, it is important to consider the strengths and limitations of currently available options. In a systematic review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we present recent developments in the field of animal lymphedema models and provide a concise comparison of ease, cost, reliability, and clinical translatability. Critical Issues: The incidence of secondary lymphedema is increasing, and there is no gold standard of treatment or cure for secondary lymphedema. Future Directions: As we iterate and create animal models that more closely characterize human lymphedema, we can achieve a deeper understanding of the pathophysiology and potentially develop effective therapeutics for patients.

The Addition of Partial or Circumferential Liposuction to Abdominoplasty Is Not Associated With a Higher Risk of Skin Necrosis.

BACKGROUND: Combining abdominoplasty with liposuction is a common practice for optimal patient aesthetic outcomes. In the past, several practitioners have argued against liposuction due to the potential for vascular insufficiency, especially with central liposuction. Despite these concerns for flap damage with resultant necrosis, the incidence of this complication has not been comprehensively investigated. OBJECTIVES: The authors therefore examined the incidence of necrotic complications, including skin and fat necrosis as well as partial/total flap loss, in patients who underwent abdominoplasty alone (AA) or abdominoplasty with partial or circumferential liposuction (APCL). METHODS: Literature searches were performed in PubMed/Medline and Embase with no query limits. For the systematic review, data from the studies were extracted into a form including primary author, publication year, study design, number of AA and APCL patients, abdominal zone(s) treated with liposuction, average lipoaspirate volume, follow-up time, necrotic complications, and revision procedures. A meta-analysis was separately performed for 13 studies that included patients who underwent both AA and APCL. RESULTS: The overall rate of necrotic complications was lower in the APCL group (0.39%) compared with the AA group (1.01%). The incidence of necrotic complications was low for all patients, with a pooled partial flap loss rate of 0.24% and a pooled skin necrosis rate of 0.23%. The forest plots revealed that patients who underwent APCL do not face a higher risk of skin necrosis or revision compared with those who underwent AA. CONCLUSIONS: Performing APCL is a safe combined procedural approach and can confer added benefits of improved patient satisfaction and aesthetic outcomes.

Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection.

ABSTRACT: Soft tissue sarcomas are a heterogenous group of malignant tumors that represent approximately 1% of adult malignancies. Although these tumors occur throughout the body, the majority involved the lower extremity. Management may involve amputation but more commonly often includes wide local resection by an oncologic surgeon and involvement of a plastic surgeon for reconstruction of larger and more complex defects. Postoperative wound complications are challenging for the surgeon and patient but also impact management of adjuvant chemotherapy and radiation therapy. To explore risk factors for wound complications, we reviewed our single-institution experience of lower-extremity soft tissue sarcomas from April 2009 to September 2016. We identified 127 patients for retrospective review and analysis. The proportion of patients with wound complications in the cohort was 43.3%. Most notably, compared with patients without wound complications, patients with wound complications had a higher proportion of immediate reconstruction (34.5% vs 15.3%; P = 0.05) and a marginally higher proportion who received neoadjuvant radiation (30.9% vs 16.7%; P = 0.06).

Role of stem cell therapies in treating chronic wounds: A systematic review.

BACKGROUND: The impairment of cutaneous wound healing results in chronic, non-healing wounds that are caused by altered wound environment oxygenation, tissue injury, and permissive microbial growth. Current modalities for the treatment of these wounds inadequately address the complex changes involved in chronic wound pathogenesis. Consequently, stem cell therapies have emerged as a potential therapeutic modality to promote cutaneous regeneration through trophic and paracrine activity. AIM: To investigate current literature regarding use of stem cell therapies for the clinical treatment of chronic, non-healing wounds. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were queried with combinations of the search terms "mesenchymal stem cells," "adult stem cells," "embryonic stem cells," "erythroid precursor cells," "stem cell therapies," and "chronic wounds" in order to find relevant articles published between the years of 2000 and 2019 to review a 20-year experience. Reference lists from the articles were reviewed to identify additional pertinent articles. Retrieved manuscripts (reviews, case reports/series, retrospective/prospective studies, and clinical trials) were evaluated by the authors for their depiction of clinical stem cell therapy use. Data were extracted from the articles using a standardized collection tool. RESULTS: A total of 43 articles describing the use of stem cell therapies for the treatment of chronic wounds were included in this review. While stem cell therapies have been explored in in vitro and in vivo applications in the past, recent efforts are geared towards assessing their clinical role. A review of the literature revealed that adipose-derived stem cells, bone marrow-derived stem cells, bone marrow-derived mononuclear cells, epidermally-derived mesenchymal stem cells, fibroblast stem cells, keratinocyte stem cells, placental mesenchymal stem cells, and umbilical cord mesenchymal stem cells have all been employed in the treatment of chronic wounds of various etiologies. Most recently, embryonic stem cells have emerged as a novel stem cell therapy with the capacity for multifaceted germ cell layer differentiation. With the capacity for self-renewal and differentiation, stem cells can enrich existing cell populations in chronic wounds in order to overcome barriers impeding the progression of wound healing. Further, stem cell therapies can be utilized to augment cell engraftment, signaling and activity, and resultant patient outcomes. CONCLUSION: Assessing observed clinical outcomes, potential for stem cell use, and relevant therapeutic challenges allows wound care stakeholders to make informed decisions regarding optimal treatment approaches for their patients' chronic wounds.

Patient Characteristics Associated with Free Nipple Graft Reduction Mammoplasty.

PURPOSE: Surgical approaches for reduction mammoplasty most commonly incorporate a parenchymal vascular pedicle. For patients with larger breasts where pedicle viability may be compromised due to excessive length, the free nipple graft (FNG) technique provides a safe alternative. Criteria for whether a patient should undergo a FNG remains controversial due to variable reports in the literature with small sample sizes and inherent surgeon-dependent bias. To address this, we sought to investigate perioperative factors associated with performing FNGs at our institution in order to better elucidate specific indications for this surgery. METHODS: A retrospective chart review was performed for 323 patients who underwent a reduction mammoplasty from August 2009 to July 2019 at Keck Hospital and LAC+USC Medical Center. Data regarding patient demographics, comorbidities, pre-operative breast characteristics, and post-operative complications were extracted. Student's t-test, Fisher's exact test, and logistic regression were performed in R. RESULTS: Of 323 patients, 15 received an FNG. Independent variables analyzed included: age, body mass index (BMI), obesity, smoking, diabetes, hypertension, surgical indication, sternal notch-to-nipple length, nipple-to-inframammary fold length, and weight of breast specimens removed. BMI, obesity, gigantomastia, and weight of specimen resected were significantly associated with use of the FNG (p < 0.001, p < 0.05, p < 0.0001, p < 0.0001, respectively). Regression analysis revealed that patients who had an average of more than 1500 g of tissue removed from each breast were 1.41 (95% CI: 1.17-1.71, p<0.001) times more likely to undergo an FNG procedure than those who had less than 1500 g of tissue removed. Demographic data and breast characteristics, such as notch-to-nipple length and nipple-to-inframammary fold length, were not significantly associated. CONCLUSION: Total weight of the breast specimens removed and BMI were significantly associated with the FNG technique. Removing more than 1500 g gof total breast tissue was also significantly correlated. These findings may guide surgeons during the decision-making process of when to use an FNG.

Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps.

Vascularized lymph node transfer (VLNT) is a promising treatment modality for lymphedema; however, how lymphatic tissue responds to ischemia has not been well defined. This study investigates the cellular changes that occur in lymph nodes in response to ischemia and reperfusion. Lymph node containing superficial epigastric artery-based groin flaps were isolated in Prox-1 EGFP rats which permits real time identification of lymphatic tissue by green fluorescence during flap dissection. Flaps were subjected to ischemia for either 1, 2, 4, or 8 hours, by temporarily occluding the vascular pedicle. Flaps were harvested after 0 hours, 24 hours, or 5 days of reperfusion. Using EGFP signal guidance, lymph nodes were isolated from the flaps and tissue morphology, cell apoptosis, and inflammatory cytokines were quantified and analyzed via histology, immunostaining, and rtPCR. There was a significant increase in collagen deposition and tissue fibrosis in lymph nodes after 4 and 8 hours of ischemia compared to 1 and 2 hours, as assessed by picrosirius red staining. Cell apoptosis significantly increased after 4 hours of ischemia in all harvest times. In tissue subject to 4 hours of ischemia, longer reperfusion periods were associated with increased rates of CD3+ and CD45+ cell apoptosis. rtPCR analysis demonstrated significantly increased expression of CXCL1/GRO-α with 2 hours of ischemia and increased PECAM-1 and TNF-α expression with 1 hour of ischemia. Significant cell death and changes in tissue morphology do not occur until after 4 hours of ischemia; however, analysis of inflammatory biomarkers suggests that ischemia reperfusion injury can occur with as little as 2 hours of ischemia.

A Pre-clinical Animal Model of Secondary Head and Neck Lymphedema.

Head and neck lymphedema (HNL) is a disfiguring disease affecting over 90% of patients treated for head and neck cancer. Animal models of lymphedema are used to test pharmacologic and microsurgical therapies; however, no animal model for HNL is described in the literature to date. In this study we describe the first reproducible rat model for HNL. Animals were subjected to two surgical protocols: (1) lymphadenectomy plus irradiation; and (2) sham surgery and no irradiation. Head and neck expansion was measured on post-operative days 15, 30 and 60. Magnetic resonance imaging (MRI) was acquired at the same time points. Lymphatic drainage was measured at day 60 via indocyanine green (ICG) lymphography, after which animals were sacrificed for histological analysis. Postsurgical lymphedema was observed 100% of the time. Compared to sham-operated animals, lymphadenectomy animals experienced significantly more head and neck swelling at all timepoints (P < 0.01). Lymphadenectomy animals had significantly slower lymphatic drainage for 6 days post-ICG injection (P < 0.05). Histological analysis of lymphadenectomy animals revealed 83% greater subcutis thickness (P = 0.008), 22% greater collagen deposition (P = 0.001), 110% greater TGFß1+ cell density (P = 0.04), 1.7-fold increase in TGFß1 mRNA expression (P = 0.03), and 114% greater T-cell infiltration (P = 0.005) compared to sham-operated animals. In conclusion, animals subjected to complete lymph node dissection and irradiation developed changes consistent with human clinical postsurgical HNL. This was evidenced by significant increase in all head and neck measurements, slower lymphatic drainage, subcutaneous tissue expansion, increased fibrosis, and increased inflammation compared to sham-operated animals.

Analysis of the Microsurgery Match from 2014 to 2018 Reveals Increased Competition for Microsurgery Fellowship Positions.

BACKGROUND: There has been no peer-reviewed published data analyzing the microsurgery match since it was established. The aim of this study is to present and analyze match data to inform residents and programs regarding outcomes. METHODS: Anonymized data were requested from the San Francisco Match, which was plotted and analyzed utilizing Pearson's Chi-square, unpaired t-test, and one-way analysis of variance (ANOVA). RESULTS: Match data was obtained from the years 2014 to 2018. The match rate decreased from 84.6% in 2015 to 67.3% in 2018, mean = 73.7 (8.29%), and (p = 0.01735). The position fill rate fluctuated from 82.9% in 2014 to 90.0% in 2016, mean = 86.5 (3.0%). In 2014 and 2015, 66.7% of applicants matched their first or second choice compared to 48.0% in 2018, mean = 58.7 (8.3%), (p =.04785). Matched applicants ranked mean = 6.6 (1.4%) programs versus 3.4 (1.3) for unmatched, (p < 0.0001). Filled programs ranked a greater number of applicants per position, mean = 8.5 (1.8%), compared to partially filled, mean = 4.6 (2.6%), and unfilled mean = 3.6 (3.4%), programs (p = 0.0014). In 2015, 55.0% of programs matched their first or second choice compared to 30.4% of programs in 2018, mean = 43.0 (10.1%). CONCLUSION: The application process for microsurgery has become more competitive. Matched applicants rank more programs than do unmatched. Fully filled programs rank more applicants per position than do unfilled or partially filled. Applicants and programs are increasingly less likely to match their top choices.

Small Peptide Modulation of Fibroblast Growth Factor Receptor 3-Dependent Postnatal Lymphangiogenesis.

BACKGROUND: The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide. METHODS AND RESULTS: Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis. CONCLUSION: FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.

Nanopatterned Bulk Metallic Glass Biosensors.

Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt-BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10-12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 µA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity.