Browsing by Author "Borschel, Gregory"
Now showing 1 - 8 of 8
Results Per Page
Sort Options
Item 07. The Mechanism of NGF Signaling In Innervation-dependent Corneal Epithelial Renewal: New Topical Treatment For Neurotrophic Keratopathy(Wolters Kluwer, 2024-04-19) Hussain, Arif; Mirmoeini, Kaveh; Mulenga, Chilando; Crabtree, Jordan; Tajdaran, Kiana; Henrique, Mario; Blum, Noam; Shalom-Feuerstein, Ruby; Borschel, Gregory; Feinberg, Konstantin; Surgery, School of MedicineBackground: Corneal clarity is essential for vision. Limbal stem cells (LSCs), the source of transparent corneal epithelial cells, are located in the basal epithelium of the limbus at the corneal-conjunctival interface, where they interact with corneal sensory nerves. Besides protection, corneal nerves may stimulate LSC activity. Pathological corneal denervation can lead to ulcers, scarring, and opacification due to impaired healing from repetitive wounds. This condition, termed Neurotrophic Keratopathy (NK), a major cause of corneal blindness, and lacks a definitive cure. Corneal nerves release various trophic factors that regulate epithelial renewal. Nerve growth factor (NGF) has shown positive effects on corneal healing and maintenance in vivo. Topical recombinant human NGF is the only FDA-approved treatment for NK. However, NGF is not efficacious in 30% of cases, requires very frequent dosing, and costs $100k per course. Moreover, NGF’s ability to heal corneal ulcers is limited. Prior studies showed NGF stimulates proliferation and maintenance of cultured human LSCs, which express TrkA and p75NTR receptors, but didn’t establish a link between NGF signaling and corneal sensory innervation-mediated trophic regulation of epithelial renewal. Furthermore, the role and molecular mechanism of NGF signaling in LSC activity remains unidentified. We hypothesize that NGF, locally expressed in its mature and premature (proNGF) forms, regulates LSC activity-dependent homeostatic and wound-induced corneal epithelial renewal via differential activation of its receptors TrkA and p75NTR, a process dependent on corneal sensory innervation. Methods: A) We conducted in vivo experiments in wild-type and mutant mice and rats to elucidate the NGF signaling mechanism in corneal innervation-dependent epithelial renewal. We examined the effect of combinations of TrkA and p75NTR agonists and antagonists on the healing of experimentally wounded corneas, both intact and surgically denervated. B) To understand the role and mechanism of NGF signaling in LSC activity and its relevance to humans, we assessed the clonogenicity of cultured human LSCs (hLSCs) by pharmacologically modulating NGF receptors, as described in (A). Results: A) While inactivation of TrkA completely prevents healing of normally innervated cornea, inactivation of p75NTR combined with a single daily dose of NGF induces complete and rapid healing of denervated de-epithelialized corneas. B) NGF or specific p75NTR inhibitor THX-B supported colonies’ formation by hLSCs that were further augmented by combination of the two compounds. Conclusions: Corneal sensory nerve-associated expression of NGF in its both forms (NGF and proNGF) regulates the proliferation and differentiation of LSCs by differentially stimulating the activity of the NGF receptors. Combined pharmacological activation and inhibition of TrkA and p75NTR, respectively, will be applied in the development of a superior NGF-based treatment of NK.Item 105. Long Term Surgical and Patient Reported Outcomes After Cross Face Nerve Graft Reconstruction in Pediatric Facial Paralysis(Wolters Kluwer, 2022) Zuo, Kevin J.; Heinelt, Martina; Ho, Emily; Borschel, Gregory; Zuker, Ronald; Surgery, School of MedicinePurpose: Free functioning muscle transfer is the gold standard for pediatric facial paralysis reconstruction and using the contralateral facial nerve for neurotization via a cross face nerve graft enables spontaneous smile restoration. Outcomes of pediatric facial reanimation beyond 10 years are not known, including how smiles change with aging and how adult patients report their facial function and quality of life. This study evaluated long term surgical and patient-reported outcomes for adults who underwent facial reanimation as children. Methods: This cross-sectional study enrolled patients who underwent facial reanimation with a staged cross face nerve graft and free gracilis muscle transfer as children at least 10 years ago. FACE-Gram software was used to quantify commissure excursion on frontal photographs in repose and maximal smile at three time points: preoperative, early postoperative within 2 years, and current (long term follow up). Patient-reported outcomes were evaluated quantitatively using the FaCE Scale and FACE-Q instruments for patient satisfaction, and qualitatively with semi-structured interviews. Results are reported as mean ± SD and parametric statistical analysis was performed with alpha of 0.05. Results: Eighteen patients who underwent facial reanimation as children more than 10 years ago were included (14 females, 5 males; 10 congenital, 8 acquired; age at stage 1 surgery 7.4 ± 3.6 years). Commissure excursion was measured as -1.3 ± 3.5 mm preoperatively, 5.9 ± 2.3 mm postoperatively within 2 years, and 7.6 ± 3.5 mm at long term follow up (mean 20.5 ± 6.9 years). Commissure excursion increased 7.2 ± 4.9 mm from preoperative to early postoperative time points (p<0.0001) and did not significantly increase or decrease at long term follow up (p>0.05). For patient reported outcomes, mean FaCE scale score for facial movement was 44/100 when including eyebrow function and 79/100 when excluding eyebrow function. Mean FaCE scale scores were 63/100 for eye comfort and 81/100 for social function. On the FACE-Q Satisfaction with Outcome scale, 17/18 respondents somewhat agreed or definitely agreed with the statement, “I am pleased with the result.” On the FACE-Q Social Function scale, 16/18 respondents somewhat agreed or definitely agreed with the statement, “I feel confident when I meet a new person.” Conclusions: Pediatric facial reanimation with cross face nerve grafting improves commissure excursion and this is maintained with aging. Adult patients report overall high satisfaction and social functioning. Ongoing ocular issues remains a problem for many patients, underscoring the importance of refining techniques for reanimation of the eye.Item 72. The Role of TrkA And P75NTR NGF Receptors in Corneal Wound Healing(Wolters Kluwer, 2022) Tajdaran, Kiana; Feinberg, Konstantin; Mirmoeini, Seyed K.; Zhang, Jennifer; Gordon, Tessa; Ali, Asim; Borschel, Gregory; Surgery, School of MedicinePurpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves may also stimulate limbal stem cells (LSCs), governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies limits their effecacy2. Development of small molecule ligands for neurotrophin receptors that have more favorable pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative conditions in recent years3. In this study, we investigated the molecular mechanism of NK and the role of the NGF receptors, TrkA and p75NTR, in corneal healing. We hypothesized that TrkA inhibition would delay corneal wound healing and p75NTR inhibition would accelerate corneal healing. Establishing the roles of these receptors may enable novel topical therapeutics for NK. Methods: We used commercially available Ntrk1 mutant mice, whose TrkA receptors are inhibited by a mammalian kinase inhibitor (1-NM-PP1)4. Ntrk1 mice (n=20) were divided into three groups, which received saline injection as a control. In one experimental group animals received TrkA inhibitor and the other group received both TrkA and p75 inhibitor for 5 days. On day six we removed the corneal epithelium with a 0.5 mm rotating brush. To measure epithelial healing, we performed digital imaging of fluorescein staining daily for four days after injury. We then harvested the corneas for immunofluorescent and biochemical analyses. Results: We observed a significant delay in corneal epithelial healing following TrkA inhibition. Further, we observed that topical p75NTR inhibition accelerated corneal wound healing. Conclusion: A selective TrkA agonist or p75NTR inhibition could represent new topical therapeutics for NK.Item QS2: Outcomes Of Pediatric Dynamic Facial Reanimation After Two Decades(Wolters Kluwer, 2021-07) Zuo, Kevin J.; Heinelt, Martina; Ho, Emily; Borschel, Gregory; Zuker, Ronald; Medicine, School of MedicinePurpose: Pediatric facial paralysis has substantial functional consequences in a growing child including impaired quality of life. Microneurovascular facial reanimation is the gold standard for smile reconstruction; however, quantitative data are lacking regarding long-term outcomes, particularly beyond 10 years. The primary objective of this study was to evaluate the long-term surgical and patient-reported outcomes after dynamic reconstruction of unilateral facial paralysis in childhood. Methods: A cross-sectional study was performed of patients in our institutional facial paralysis database (1978-2008) who underwent dynamic reconstruction of unilateral facial paralysis 20 or more years ago. All patients were treated as children with a staged cross face nerve graft and free functioning muscle transfer. Frontal facial photographs in repose and maximal smile prior to surgery, within 2 years post-surgery, and at long term follow-up were analyzed using the MEEI Face-Gram software for commissure excursion. Patient-reported outcomes were obtained using the FaCE Scale for subjective facial impairment and disability, as well as the FACE-Q Satisfaction with Outcome and FACE-Q Social Function scales. Results are reported as median [IQR] and non-parametric statistical analysis was performed with alpha of 0.05. Results: Eleven patients were included with long term follow-up of 23.7 [5.6] years (6 females, 5 males; 5 congenital, 6 acquired; age at surgery 7.3 [6.3] years). For surgical quantitative measures, commissure excursion significantly improved from prior to surgery (-1.3 [7.4] mm) compared to follow up within 2 years post-surgery (7.0 [1.7] mm) (p<0.05) and from prior to surgery compared to long term follow-up (8.3 [4.9] mm) (p<0.001). There was no statistically significant difference in commissure excursion within 2 years post-surgery and at long term follow-up (p>0.05). For patient-reported outcomes, median FaCE Scale scores showed good function for social function (81/100), oral function (88/100), facial comfort (92/100), and overall score (75/100). On the FACE-Q Satisfaction with Outcome scale, 10/11 respondents somewhat agreed or definitely agreed with the statement, “I am pleased with the result.” On the FACE-Q Social Function scale, 10/11 respondents somewhat agreed or definitely agreed with the statements, “I make a good first impression” and “I feel confident when I participate in group situations.” Conclusion: Dynamic reconstruction of unilateral facial paralysis in young children improves commissure excursion that is maintained at long-term follow up. As adults, these patients report a high level of satisfaction and social functioning with their smile reconstruction.Item QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing(Wolters Kluwer, 2021-07-26) Tajdaran, Kiana; Feinberg, Konstantin; Mirmoeini, Seyed Kaveh; Zhang, Jennifer; Gordon, Tessa; Borschel, Gregory; Surgery, School of MedicinePurpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is the human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies make this therapeutic approach less effective2. Development of the small molecule ligands for neurotrophins receptors that have better pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative conditions in the recent years3. In this study, we were prompted to investigate the molecular mechanism of NK and the role of NGF receptors, TrkA and p75NTR, in corneal healing. We hypothesized that TrkA inhibition would delay corneal wound healing and p75NTR inhibition accelerates corneal healing. This knowledge will lay the basis for a new non-invasive approach for NK. Methods: For this experiment, we took advantage of commercially available Ntrk1 mutant mice, which allow for pharmacological inhibition of TrkA receptor with an inhibitor known as not mammalian kinase inhibitor (1-NM-PP1)4. Ntrk1 mice (n=20) were divided into three groups, which received saline injection as a control. In one experimental group animals were received TrkA inhibitor and the other group received both TrkA and p75 inhibitor for 5 days. On day six we removed the corneal epithelium with a 0.5 mm rotating brush. To measure epithelial healing, we performed digital imaging of fluorescein staining daily for four days after injury. We then harvested the corneas for immunofluorescent and biochemical analyses. Results: Our results show a significant delay in corneal epithelial healing following TrkA inhibition and acceleration in corneal healing after p75NTR inhibition. Conclusion: A selective TrkA agonist or p75NTR inhibitors could be a new therapeutic approach for NK.Item SO9. New Hope For Patients With Neurotrophic Keratopathy: Molecular Interactions Governing Nerve-mediated Control Of Corneal Epithelial Renewal And Wound Healing(Wolters Kluwer, 2025-05-16) Hussain, Arif; Mirmoeini, Kaveh; Mulenga, Chilando M.; Crabtree, Jordan; Tajdaran, Kiana; Henriquez, Mario; Feinberg, Konstantin; Borschel, Gregory; Surgery, School of MedicinePURPOSE: Corneal clarity, essential for vision, is maintained by limbal stem cells (LSCs), which generate transparent limbal epithelial cells. Corneal sensory nerves, beyond their protective role, are believed to stimulate LSCs via unknown mechanisms. Neurotrophic keratopathy (NK), caused by absent corneal innervation from congenital or acquired etiologies (e.g., tumors, trauma, infections), leads to blindness. Corneal nerve-associated Schwann cells (SCs) play a crucial role in wound healing and epithelial maintenance. Our scRNA-seq studies suggest that several trophic factors secreted by SCs regulate LSC activity, identifying pleiotrophin (PTN) as a novel SC-derived regulator of corneal renewal, particularly when combined with ciliary neurotrophic factor (CNTF). METHODS: In our two NK models, either local ablation of SC or surgical corneal denervation causes corneal ulceration and prevents healing of experimental corneal ulcers. To define the role of PTN in corneal epithelial renewal, we tested the effects of topical recombinant PTN alone or with other trophic factors on the healing of surgically denervated or genetically SC-ablated deepithelialized rodent corneas. RESULTS: (i) PTN alone induced rapid healing, and, (ii) when applied together with (CNTF), induced complete recovery of corneal clarity. CONCLUSION: Under conditions of denervation or SC loss, exogenous PTN with CNTF rescue corneal epithelial renewal. These findings will be leveraged towards the development of topical treatments for NK.Item The Role of Early Latissimus Dorsi Tendon Transfers for Shoulder Movement and Stability in Neonatal Brachial Plexus Injury(Wolters Kluwer, 2023-10-18) Gross, Jeffrey; Bhagat, Neel; Mulenga, Chilando; Singh, Nikhi; Borschel, Gregory; Adkinson, Joshua; Graduate Medical Education, School of MedicineINTRODUCTION: Neonatal brachial plexus injury (BPI) is a rare but devastating complication of birth. An upper trunk BPI can result in the loss of shoulder external rotation and abduction and often leads to glenohumeral joint dysplasia (GJD). The latissimus dorsi/teres major tendon transfer (LTT) is a procedure used to restore external rotation and shoulder abduction and potentially reduce the incidence of GJD. Historically, this tendon transfer has been performed when the child is older and has demonstrated impaired shoulder function. In this study, we sought to assess feasibility and short-term outcomes of LTT combined with BPI reconstruction. METHODS: A retrospective review of patients was performed. Inclusion criteria were patients under 18 years of age at Riley Children’s Hospital with BPI who underwent LTT between 2021-2022. RESULTS: Eighteen patients underwent LTT between 2021-2022 at the mean age of 2.2 +/- 2.2 years. Five patients (27.8%) underwent the transfer concurrently with BPI nerve reconstruction, 8 (44.4%) underwent staged LTT, and 5 (27.8%) patients underwent LTT with no previous or concurrent BPI reconstruction. Of the 8 patients that underwent staged repair, 7/8 (88%) had MRI evidence of GJD prior to their tendon transfer. There were no major complications in any subgroup. Average follow-up was 7.54 months. The mean age at surgery for patients undergoing staged LTT was 2.1 years old compared to 6 months in the concurrent group. In the staged cohort, available post-operative mean AMS scores were 3.5 for shoulder abduction, 1.67 for shoulder external rotation. and 4.83 for shoulder forward flexion. In the concurrent cohort, mean AMS scores were 3.2 for shoulder abduction, 1.8 for external rotation, and 3.6 for shoulder forward flexion. CONCLUSIONS: In this study, we found that LTT can be safely and efficiently combined with BPI reconstruction. Patients in the concurrent surgery cohort achieved similar shoulder functional scores as those in the staged surgery cohort, but these scores were achieved at a younger age (i.e.1.5 years earlier) and without a second surgery. In addition, a simultaneous or early approach may provide the very young pediatric patient shoulder stability needed to prevent GJD while also avoiding the need for a second anesthetic exposure. Future studies will focus on comparative assessment of long-term shoulder functional outcomes.Item Using Big Data to Assess Legitimacy of Plastic Surgery Information on Social Media(Oxford Academic, 2022-01) Chartier, Christian; Lee, Justine C.; Borschel, Gregory; Chandawarkar, Akash; Surgery, School of MedicineBackground The proliferation of social media in plastic surgery poses significant difficulties for the public in determining legitimacy of information. This work proposes a system based on social network analysis (SNA) to assess the legitimacy of information contributors within a plastic surgery community. Objectives The aim of this study was to quantify the centrality of individual or group accounts on plastic surgery social media by means of a model based on academic plastic surgery and a single social media outlet. Methods To develop the model, a high-fidelity, active, and legitimate source account in academic plastic surgery (@psrc1955, Plastic Surgery Research Council) appearing only on Instagram (Facebook, Menlo Park, CA) was chosen. All follower-followed relationships were then recorded, and Gephi (https://gephi.org/) was used to compute 5 different centrality metrics for each contributor within the network. Results In total, 64,737 unique users and 116,439 unique follower-followed relationships were identified within the academic plastic surgery community. Among the metrics assessed, the in-degree centrality metric is the gold standard for SNA, hence this metric was designated as the centrality factor. Stratification of 1000 accounts by centrality factor demonstrated that all of the top 40 accounts were affiliated with a plastic surgery residency program, a board-certified academic plastic surgeon, a professional society, or a peer-reviewed journal. None of the accounts in the top decile belonged to a non–plastic surgeon or non-physician; however, this increased significantly beyond the 50th percentile. Conclusions A data-driven approach was able to identify and successfully vet a core group of interconnected accounts within a single plastic surgery subcommunity for the purposes of determining legitimate sources of information.