- Treatment modes for EGFR mutations in patients with brain metastases from non-small cell lung cancer: controversy, causes, and solutions TRANSLATIONAL LUNG CANCER RESEARCH 2019; 8 (4): 524–31
- Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases WORLD NEUROSURGERY 2019; 126: E1399–E1411
- Stereotactic radiosurgery for resected brain metastases: Does the surgical corridor need to be treated? AMER SOC CLINICAL ONCOLOGY. 2019
Neurological Adverse Effects Due to Programmed Death (PD-1) Inhibitors
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000475965900259
Challenges in Translating from Bench to Bed-Side: Pro-Angiogenic Peptides for Ischemia Treatment.
Molecules (Basel, Switzerland)
2019; 24 (7)
We describe progress and obstacles in the development of novel peptide-hydrogel therapeutics for unmet medical needs in ischemia treatment, focusing on the development and translation of therapies specifically in peripheral artery disease (PAD). Ischemia is a potentially life-threatening complication in PAD, which affects a significant percentage of the elderly population. While studies on inducing angiogenesis to treat PAD were started two decades ago, early results from animal models as well as clinical trials have not yet been translated into clinical practice. We examine some of the challenges encountered during such translation. We further note the need for sustained angiogenic effect involving whole growth factor, gene therapy and synthetic growth factor strategies. Finally, we discuss the need for tissue depots for de novo formation of microvasculature. These scaffolds can act as templates for neovasculature development to improve circulation and healing at the preferred anatomical location.
View details for DOI 10.3390/molecules24071219
View details for PubMedID 30925755
Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases.
BACKGROUND: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies.METHODS: We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving 'concurrent' SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure (LF), distant intracranial failure (DIF), extracranial failure (EF), and adverse radiation effect (ARE) were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models.RESULTS: A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses demonstrated that concurrent SRS-ICI therapy is associated with higher rates of ARE (6.4% vs 2.0% at 1 year; multivariable HR 4.47; 95% CI, 1.57-12.73; p=0.005), lower rates of EF (69.7% vs 80.8% at 1 year; multivariable HR 0.60; 95% CI, 0.42-0.87; p=0.007), and better overall survival (48.6% vs 25.4% at 1 year; multivariable HR 0.57; 95% CI, 0.33-0.99; p=0.044) as compared to non-concurrent therapy. SRS-ICI timing was not associated with LF or DIF.CONCLUSIONS: Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.
View details for PubMedID 30902777
- Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues MOLECULAR CANCER 2019; 18
Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues.
2019; 18 (1): 21
Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism forradiation brain necrosis development. Bevacizumab alleviates brain edema symptoms caused by radiation brain necrosis through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' Karnofsky performance status (KPS) scores and brain necrosis imaging. However, necrosis is irreversible, and hypoxia and ischemia localized in the brain necrosis area may easily lead to radiation brain necrosis recurrence after bevacizumab is discontinued. Further studies are necessary to investigate brain necrosis diagnoses, bevacizumab indications, and the optimal mode of administration, bevacizumab resistance and necrosis with a residual or recurrent tumor.
View details for PubMedID 30732625
- False News of a Cannabis Cancer Cure CUREUS 2019; 11 (1)
Waiting it out: consultation delays prolong in-patient length of stay.
Postgraduate medical journal
Decreasing delays for hospitalised patients results in improved hospital efficiency, increased quality of care and decreased healthcare expenditures. Delays in subspecialty consultations and procedures can cause increased length of stay due to reasons outside of necessary medical care.To quantify, describe and record reasons for delays in consultations and procedures for patients on the general medicine wards.We conducted weekly audits of all admitted patients on five Internal Medicine teams over 8 weeks. A survey was reviewed with attending physicians and residents on five internal medicine teams to identify patients with a delay due to consultation or procedure, quantify length of delay and record reason for delay.During the study period, 316 patients were reviewed and 48 were identified as experiencing a total of 53 delays due to consultations or procedures. The average delay was 1.8 days for a combined total of 83 days. Top reasons for delays included scheduling, late response to page and a busy service. The frequency in length of consult delays vary among different specialties. The highest frequency of delays was clustered in procedure-heavy specialties.This report highlights the importance of reviewing system barriers that lead to delayed service in hospitals. Addressing these delays could lead to reductions in length of stay for inpatients.
View details for PubMedID 30674619
Increase of secondary mutations may be a drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with tyrosine kinase inhibitor.
Journal of Cancer
2019; 10 (22): 5371–76
Objective: To investigate changes in the secondary mutations of tumor in a drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with tyrosine kinase inhibitor (TKI). Methods: Lung adenocarcinoma cell line PC9 in vitro and xenograft model in nude mice were used to observe tumor inhibitory effects and drug-resistance under the effect of radiation therapy combined with erlotinib through apoptosis detection through in vitro survival curve and in vivo growth curve; changes in gene mutations before and after drug-resistance in nude mice xenografts were observed by the next generation sequencing, and the relationship between cancer drug-resistance and radiation therapy combined with TKI was observed. Results: Radiation therapy combined with erlotinib had a more reliable radio-sensitizing effect in vitro and in vivo, however, there were several drug-resistant tumor cells. Meanwhile, radiation therapy combined with erlotinib could significantly increase the number of mutations in tumor genes. The whole genome sequencing showed that the secondary mutation in the combined treatment group significantly increased in comparison with those of the single treatment group and the blank control group. Conclusion: The increase of secondary mutations may be an important drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with TKI, which provided further space exploration under the combined action of radiation and TKI.
View details for DOI 10.7150/jca.35247
View details for PubMedID 31632481
View details for PubMedCentralID PMC6775686
Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study
ONCOTARGETS AND THERAPY
2019; 12: 8447–53
To investigate the treatment efficacy of ultra-low-dose bevacizumab for cerebral radiation necrosis.Patients with cerebral radiation necrosis after stereotactic radiotherapy (SRT) confirmed by imaging were included. Bevacizumab (1 mg/kg, once every three weeks, for at least three continuous treatments) was administered. The primary endpoints included change in cerebral necrosis symptoms, volume of intracranial edema, and changes in MRI signals. The secondary endpoints were adverse reactions of bevacizumab treatment.In total, 21 patients were included in this study, all of whom received SRT between December 2016 and February 2019, developed cerebral radiation necrosis, and were treated with bevacizumab. Twenty patients were symptomatic from radiation necrosis, and the symptoms were alleviated in 18 patients (90%). Twenty patients had intracranial edema, and the grade of edema index (EI) was improved in 19 patients (95%). The intensity of the intracranial-enhanced MRI signals was significantly reduced in 20 patients (95.24%). The adverse reactions of bevacizumab treatment were mild, and no adverse reactions more severe than grade 2 were found.The preliminary results showed that ultra-low-dose bevacizumab had high efficacy for treating cerebral radiation necrosis, and could be a valid alternative to the standard-dose bevacizumab.Chinese clinical trial registry (ChiCTR-IOD-16009803).
View details for DOI 10.2147/OTT.S223258
View details for Web of Science ID 000489590900001
View details for PubMedID 31632089
View details for PubMedCentralID PMC6792824
False News of a Cannabis Cancer Cure.
2019; 11 (1): e3918
Background There is increasing concern among healthcare communities about the misinformation online about using cannabis to cure cancer. We have characterized this online interest in using cannabis as a cancer treatment and the propagation of this information on social media. Materials & methods We compared search activity over time for cannabis and cancer versus standard cancer therapies using Google Trends' relative search volume (RSV) tool and determined the impact of cannabis legalization. We classified news on social media about cannabis use in cancer as false, accurate, or irrelevant. We evaluated the cannabis-related social media activities of cancer organizations. Results The online search volume for cannabis and cancer increased at 10 times the rate of standard therapies (RSV 0.10/month versus 0.01/month, p<0.001), more so in states where medical or recreational cannabis is legal. The use of cannabis as a cancer cure represented the largest category (23.5%) of social media content on alternative cancer treatments. The top false news story claiming cannabis as a cancer cure generated 4.26 million engagements on social media, while the top accurate news story debunking this false news generated 0.036 million engagements. Cancer organizations infrequently addressed cannabis (average 0.7 Tweets; 0.4 Facebook posts), with low influence compared to false news (average 5.6 versus 527 Twitter retweets; 98 versus 452,050 Facebook engagements, p<0.001). Conclusions These findings reveal a growing interest in cannabis use as a cancer cure, and a crucial opportunity for physicians and medical organizations to communicate accurate information about the role of cannabis in cancer to patients, caregivers, and the general public.
View details for PubMedID 30931189
View details for PubMedCentralID PMC6426557
- Increase of secondary mutations may be a drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with tyrosine kinase inhibitor JOURNAL OF CANCER 2019; 10 (22): 5371–76
Treatment modes for EGFR mutations in patients with brain metastases from non-small cell lung cancer: controversy, causes, and solutions.
Translational lung cancer research
2019; 8 (4): 524–31
Brain metastasis from non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is a hot research topic, but also a difficulty in targeted NSCLC therapy, and is also the focus of controversy in the field of lung cancer treatment. According to medical oncology, asymptomatic patients were initially treated with targeted therapy, followed by local radiotherapy when symptoms present or disease progresses. However, from the perspective of the discipline of radiotherapy, brain metastases need to be treated before drug resistance, as it may affect survival. Controversies between disciplines have brought much confusion to the treatment choices of clinicians. We summarized and discussed relevant literatures in this article to seek the truth in providing reference in clinical practice for treating diseases and solving problems.
View details for DOI 10.21037/tlcr.2019.07.03
View details for PubMedID 31555525
View details for PubMedCentralID PMC6749108
Waiting it out: Consultation delays prolong in-patient length of stay
Postgraduate Medical Journal
View details for DOI 10.1136/postgradmedj-2018-136269
Stereotactic radiosurgery for resected brain metastases: single-institutional experience of over 500 cavities.
International journal of radiation oncology, biology, physics
Post-operative stereotactic radiosurgery (SRS) has less detrimental impact on cognition and quality of life compared to whole brain radiotherapy (WBRT) and is increasingly used for resected brain metastases (BMs). Post-operative SRS techniques are not standardized, and there is a concern for a different pattern of failure following post-operative SRS compared to WBRT. We aim to study the efficacy, toxicity, and failure pattern of post-operative SRS.We retrospectively reviewed outcomes of patients with resected BMs treated with post-operative SRS between 2007 and 2018. Overall survival (OS) and cumulative incidences of local failure (LF), overall distant intracranial failure [distant parenchymal failure (DPF), nodular leptomeningeal disease (nLMD), classical leptomeningeal disease (cLMD)], and adverse radiation effect (ARE) were reported. Neurological death was determined for patients with leptomeningeal disease (LMD).A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and OS after SRS were 10.1 months [interquartile range (IQR) 3.6-20.7 months] and 13.9 months [95% confidence interval (CI) 11.8-15.2 months], respectively. At 12 months, event rates were 7% (95% CI 5%-10%) for LF, 9% (95% CI 7%-12%) for ARE, 44% (95% CI 40%-49%) for overall distant intracranial failure, 37% (95% CI 33%-42%) for DPF and 13% (95% CI 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 versus 11.2 months, p<0.01) and a higher proportion of neurological death (67% versus 41%, p=0.02). A total of 15% of patients ultimately received WBRT.We report the largest clinical experience of post-operative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.
View details for DOI 10.1016/j.ijrobp.2019.11.022
View details for PubMedID 31785338
Stereotactic Radiosurgery for Pediatric and Adult Intracranial and Spinal Ependymomas.
Stereotactic and functional neurosurgery
We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma.We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method.Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2-157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11-43) and 42% (95% CI 22-60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects.SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.
View details for DOI 10.1159/000502653
View details for PubMedID 31590165
De novo AVM formation following venous sinus thrombosis and prior AVM resection in adults: report of 2 cases.
Journal of neurosurgery
Brain arteriovenous malformations (AVMs) are traditionally considered congenital lesions, arising from aberrant vascular development during the intrauterine period. Rarely, however, AVMs develop in the postnatal period. Individual case reports of de novo AVM formation in both pediatric and adult patients have challenged the traditional dogma of a congenital origin. Instead, for these cases, a dynamic picture is emerging of AVM growth and development, initially triggered by ischemic and/or traumatic events, coupled with genetic predispositions. A number of pathophysiological descriptions involving aberrant angiogenic responses following trauma, hemorrhage, or inflammation have been proposed, although the exact etiology of these lesions remains to be elucidated. Here, the authors present 2 cases of de novo AVM formation in adult patients. The first case involves the development of an AVM following a venous sinus thrombosis and to the authors' knowledge is the first of its kind to be reported in the literature. They also present a case in which an elderly patient with a previously ruptured AVM developed a second AVM in the contralateral hemisphere 11 years later. In addition to presenting these cases, the authors propose a possible mechanism for de novo AVM development in adult patients following ischemic injury.
View details for DOI 10.3171/2016.9.JNS161710
View details for PubMedID 28186446
Collar Sign in Incompletely Occluded Aneurysms after Pipeline Embolization: Evaluation with Angiography and Optical Coherence Tomography
AMERICAN JOURNAL OF NEURORADIOLOGY
2017; 38 (2): 323-326
Flow diversion with the Pipeline Embolization Device has emerged as an attractive treatment for cerebral aneurysms. Processes involved in aneurysm occlusion include changes in intra-aneurysmal hemodynamics and endothelialization of the device. Here, we call attention to a radiographic sign not previously reported that is detected in incompletely occluded aneurysms after treatment with the Pipeline Embolization Device at angiographic follow-up and referred to as the "collar sign."A retrospective review of all patients who underwent placement of a Pipeline Embolization Device for cerebral aneurysms between January 2014 and May 2016 was performed. All aneurysms found to show the collar sign at follow-up were included. Optical coherence tomography was performed in 1 case.One hundred thirty-five aneurysms were treated in 115 patients. At angiographic follow-up, 17 (10.7%) aneurysms were found to be incompletely occluded. Ten (58.8%) of these aneurysms (average diameter, 7.9 ± 5.0 mm) were found to have the collar sign at angiographic follow-up (average, 5.5 ± 1.0 months). Four (40.0%) of the aneurysms underwent a second angiographic follow-up (average, 11.0 ± 0.9 months) after treatment, and again were incompletely occluded and showing the collar sign. Two patients underwent retreatment with a second Pipeline Embolization Device. Optical coherence tomography showed great variability of endothelialization at the proximal end of the Pipeline Embolization Device.The collar sign appears to be indicative of endothelialization, but continued blood flow into the aneurysm. This is unusual given the processes involved in aneurysm occlusion after placement of the Pipeline Embolization Device and has not been previously reported.
View details for DOI 10.3174/ajnr.A5010
View details for Web of Science ID 000393170100024
View details for PubMedID 28056454
Factors predicting reoperation of chronic subdural hematoma following primary surgical evacuation.
Journal of neurosurgery
OBJECTIVE Chronic subdural hematoma (CSDH) is commonly encountered in neurosurgical practice. However, surgical evacuation remains complicated by a high rate of reoperation. The optimal surgical approach to reduce the reoperation rate has not been determined. In the current study, the authors evaluated the prognostic value of clinical and radiographic factors to predict reoperation in the context of CSDH. METHODS A retrospective review of 325 CSDH patients admitted to an academic medical center in the United States, between 2006 and 2016, was performed. Clinical and radiographic factors predictive of the need for CSDH reoperation were identified on univariable and multivariable analyses. RESULTS Univariable analysis showed that warfarin use, clopidogrel use, mixed hypo- and isointensity on T1-weighted MRI, greater preoperative midline shift, larger hematoma/fluid residual on first postoperative day CT, lesser decrease in hematoma size after surgery, use of monitored anesthesia care (MAC), and lack of intraoperative irrigation correlated with a significantly higher rate of reoperation. Multivariable analysis, however, showed that only the presence of loculation, clopidogrel or warfarin use, and percent of hematoma change after surgery significantly predicted the need for reoperation. Our results showed that 0% (no reduction), 50%, and 100% hematoma maximum thickness change (complete resolution of hematoma after surgery) were associated with a 41%, 6%, and < 1% rate of reoperation, respectively. The use of drains, either large diameter or small caliber, did not have any effect on the likelihood of reoperation. CONCLUSIONS Among many factors, clopidogrel or warfarin use, hematoma loculation on preoperative CT, and the amount of hematoma evacuation on the first postoperative CT were the strongest predictors of reoperation.
View details for DOI 10.3171/2017.6.JNS17130
View details for PubMedID 29243977
Treatment of hind limb ischemia using angiogenic peptide nanofibers
2016; 98: 113-119
For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.
View details for DOI 10.1016/j.biomaterials.2016.04.032
View details for PubMedID 27182813
Development of peptide inhibitors of HIV transmission.
2016; 1 (2): 109–21
Treatment of HIV has long faced the challenge of high mutation rates leading to rapid development of resistance, with ongoing need to develop new methods to effectively fight the infection. Traditionally, early HIV medications were designed to inhibit RNA replication and protein production through small molecular drugs. Peptide based therapeutics are a versatile, promising field in HIV therapy, which continues to develop as we expand our understanding of key protein-protein interactions that occur in HIV replication and infection. This review begins with an introduction to HIV, followed by the biological basis of disease, current clinical management of the disease, therapeutics on the market, and finally potential avenues for improved drug development.
View details for DOI 10.1016/j.bioactmat.2016.09.004
View details for PubMedID 29744399
View details for PubMedCentralID PMC5883972
Nanofibrous Snake Venom Hemostat
ACS BIOMATERIALS SCIENCE & ENGINEERING
2015; 1 (12): 1300-1305
Controlling perioperative bleeding is of critical importance to minimize hemorrhaging and fatality. Patients on anticoagulant therapy such as heparin have diminished clotting potential and are at risk for hemorrhaging. Here we describe a self-assembling nanofibrous peptide hydrogel (termed SLac) that on its own can act as a physical barrier to blood loss. SLac was loaded with snake-venom derived Batroxobin (50 μg/mL) yielding a drug-loaded hydrogel (SB50). SB50 was potentiated to enhance clotting even in the presence of heparin. In vitro evaluation of fibrin and whole blood clotting helped identify appropriate concentrations for hemostasis in vivo. Batroxobin-loaded hydrogels rapidly (within 20s) stop bleeding in both normal and heparin-treated rats in a lateral liver incision model. Compared to standard of care, Gelfoam, and investigational hemostats such as Puramatrix, only SB50 showed rapid liver incision hemostasis post surgical application. This snake venom-loaded peptide hydrogel can be applied via syringe and conforms to the wound site resulting in hemostasis. This demonstrates a facile method for surgical hemostasis even in the presence of anticoagulant therapies.
View details for DOI 10.1021/acsbiomaterials.5b00356
View details for PubMedID 26753175
Controlled Angiogenesis in Peptide Nanofiber Composite Hydrogels
ACS BIOMATERIALS SCIENCE & ENGINEERING
2015; 1 (9): 845-854
Multidomain peptide (MDP) nanofibers create scaffolds that can present bioactive cues to promote biological responses. Orthogonal self-assembly of MDPs and growth-factor-loaded liposomes generate supramolecular composite hydrogels. These composites can act as delivery vehicles with time-controlled release. Here we examine the controlled release of placental growth factor-1 (PlGF-1) for its ability to induce angiogenic responses. PlGF-1 was loaded either in MDP matrices or within liposomes bound inside MDP matrices. Scaffolds showed expected rapid infiltration of macrophages. When released through liposomes incorporated in MDP gels (MDP(Lipo)), PlGF-1 modulates HUVEC VEGF receptor activation in vitro and robust vessel formation in vivo. These loaded MDP(Lipo) hydrogels induce a high level of growth-factor-mediated neovascular maturity. MDP(Lipo) hydrogels offer a biocompatible and injectable platform to tailor drug delivery and treat ischemic tissue diseases.
View details for DOI 10.1021/acsbiomaterials.5b00210
View details for PubMedID 26925462
Self-assembling multidomain peptides tailor biological responses through biphasic release
2015; 52: 71-78
Delivery of small molecules and drugs to tissues is a mainstay of several tissue engineering strategies. Next generation treatments focused on localized drug delivery offer a more effective means in dealing with refractory healing when compared to systemic approaches. Here we describe a novel multidomain peptide hydrogel that capitalizes on synthetic peptide chemistry, supramolecular self-assembly and cytokine delivery to tailor biological responses. This material is biomimetic, shows shear stress recovery and offers a nanofibrous matrix that sequesters cytokines. The biphasic pattern of cytokine release results in the spatio-temporal activation of THP-1 monocytes and macrophages. Furthermore, macrophage-material interactions are promoted without generation of a proinflammatory environment. Subcutaneous implantation of injectable scaffolds showed a marked increase in macrophage infiltration and polarization dictated by cytokine loading as early as 3 days, with complete scaffold resorption by day 14. Macrophage interaction and response to the peptide composite facilitated the (i) recruitment of monocytes/macrophages, (ii) sustained residence of immune cells until degradation, and (iii) promotion of a pro-resolution M2 environment. Our results suggest the potential use of this injectable cytokine loaded hydrogel scaffold in a variety of tissue engineering applications.
View details for DOI 10.1016/j.biomaterials.2015.01.079
View details for Web of Science ID 000353091000006
View details for PubMedID 25818414
View details for PubMedCentralID PMC4613801
Drug-Triggered and Cross-Linked Self-Assembling Nanofibrous Hydrogels
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2015; 137 (14): 4823-4830
Self-assembly of multidomain peptides (MDP) can be tailored to carry payloads that modulate the extracellular environment. Controlled release of growth factors, cytokines, and small-molecule drugs allows for unique control of in vitro and in vivo responses. In this study, we demonstrate this process of ionic cross-linking of peptides using multivalent drugs to create hydrogels for sustained long-term delivery of drugs. Using phosphate, heparin, clodronate, trypan, and suramin, we demonstrate the utility of this strategy. Although all multivalent anions result in good hydrogel formation, demonstrating the generality of this approach, suramin led to the formation of the best hydrogels per unit concentration and was studied in greater detail. Suramin ionically cross-linked MDP into a fibrous meshwork as determined by scanning and transmission electron microscopy. We measured material storage and loss modulus using rheometry and showed a distinct increase in G' and G″ as a function of suramin concentration. Release of suramin from scaffolds was determined using UV spectroscopy and showed prolonged release over a 30 day period. Suramin bioavailability and function were demonstrated by attenuated M1 polarization of THP-1 cells compared to positive control. Overall, this design strategy has allowed for the development of a novel class of polymeric delivery vehicles with generally long-term release and, in the case of suramin, cross-linked hydrogels that can modulate cellular phenotype.
View details for DOI 10.1021/jacs.5b01549
View details for PubMedID 25831137
Highly Angiogenic Peptide Nanofibers
2015; 9 (1): 860-868
Major limitations of current tissue regeneration approaches using artificial scaffolds are fibrous encapsulation, lack of host cellular infiltration, unwanted immune responses, surface degradation preceding biointegration, and artificial degradation byproducts. Specifically, for scaffolds larger than 200-500 μm, implants must be accompanied by host angiogenesis in order to provide adequate nutrient/waste exchange in the newly forming tissue. In the current work, we design a peptide-based self-assembling nanofibrous hydrogel containing cell-mediated degradation and proangiogenic moieties that specifically address these challenges. This hydrogel can be easily delivered by syringe, is rapidly infiltrated by cells of hematopoietic and mesenchymal origin, and rapidly forms an extremely robust mature vascular network. Scaffolds show no signs of fibrous encapsulation and after 3 weeks are resorbed into the native tissue. These supramolecular assemblies may prove a vital paradigm for tissue regeneration and specifically for ischemic tissue disease.
View details for DOI 10.1021/nn506544b
View details for Web of Science ID 000348619000094
View details for PubMedID 25584521
View details for PubMedCentralID PMC4370274