Smriti Agrawal, Ph.D.

Medical technology company Lazarus 3D is introducing a new way for surgeons to rehearse on models that look, feel and cut like their specific patients. In an interview with Dr. Smriti Zaneveld, this CNN feature unveils the future of precision surgical care.

It may be hard to believe but sometimes surgeons will rehearse a surgery on things like a bell pepper, mainly because it does an okay job of mimicking skin. But Texas-born Lazarus 3D thought there must be a better way. So, they developed a system to transform patient imaging into 3D printed organs so surgeons can rehearse with confidence.
Dr. Smriti Zaneveld is the co-founder & president of Lazarus 3D. She says her team came up with this new technology after a shuttle bus ride at the Texas… Show more

It may be hard to believe but sometimes surgeons will rehearse a surgery on things like a bell pepper, mainly because it does an okay job of mimicking skin. But Texas-born Lazarus 3D thought there must be a better way. So, they developed a system to transform patient imaging into 3D printed organs so surgeons can rehearse with confidence.
Dr. Smriti Zaneveld is the co-founder & president of Lazarus 3D. She says her team came up with this new technology after a shuttle bus ride at the Texas Medical Center.
“So, I was talking to a surgeon one day he told me had been practicing on a bell pepper,” Dr. Zaneveld said. “And I was like you’re kidding right.”
She thought there had to be a better way. “With soft tissue, this was not being addressed because the technology did not exist,” Dr. Zaneveld said. “So, this is why it’s revolutionary. We built that technology.”
They use MRI/CT scans to build an exact soft tissue replica of the patient’s organ so a doctor can rehearse before surgery. “This is a kidney of a patient with kidney cancer,” Dr. Zaneveld said as she held a replica of the patient’s kidney. “We built Pre-Sure for this patient where the surgeon was basically using it to first assess the anatomy & the critical structures that are surrounding the tumor. The models even bleed & have tension like real organs, giving doctors a life-like feel. The Pre-Sure rehearsal & the procedure look almost identical when the video is put side to side on the screen.
“This is a tumor here on this patient’s rib,” Thoracic Surgeon with Austin’s Cardiothoracic Institute Dr. Rachel Medbery said as she pointed to the patient’s scan.
Dr. Medbery has not used Pre-Sure yet but says it could be a game-changer for pre-op rehearsal. “In my case, if I’m dealing with a large tumor either in the lung or near the heart or the chest wall, the ability to practice ahead of time to know what I can and can’t get away with safely in the operating room would be huge,” Dr. Medbery said. Show less

Most renal tumours can be treated with a partial nephrectomy, with robot-assisted partial nephrectomy becoming the new gold standard. This procedure is challenging to learn in a live setting, especially the enucleation and renorraphy phases. In this study, we attempted to evaluate face, content, & preliminary construct validity of a 3D-printed silicone renal tumour model in robotic training for robot-assisted partial nephrectomy.

Face and content validity of our 3D renal tumour model… Show more

Most renal tumours can be treated with a partial nephrectomy, with robot-assisted partial nephrectomy becoming the new gold standard. This procedure is challenging to learn in a live setting, especially the enucleation and renorraphy phases. In this study, we attempted to evaluate face, content, & preliminary construct validity of a 3D-printed silicone renal tumour model in robotic training for robot-assisted partial nephrectomy.

Face and content validity of our 3D renal tumour model were demonstrated. The vast majority of participants found the model realistic and useful for training and for evaluation. To evaluate construct & predictive validity, we require further research, aiming to compare the results of 3D-model trained surgeons with those of untrained surgeons in real-life surgery.

Keywords: 3D‐printed; GEARS score; partial nephrectomy; robot‐assisted surgery; training model; validity.

Show less

Much of the complexity of the eukaryotic cell transcriptome is due to the alternative splicing of mRNA. However, knowledge on how transcriptome complexity is translated into functional complexity remains limited. For example, although different isoforms of a gene may show distinct temporal and spatial expression patterns, it is largely unknown whether these isoforms encode proteins with distinct functions matching their expression pattern. In this report, we investigated the function and… Show more

Much of the complexity of the eukaryotic cell transcriptome is due to the alternative splicing of mRNA. However, knowledge on how transcriptome complexity is translated into functional complexity remains limited. For example, although different isoforms of a gene may show distinct temporal and spatial expression patterns, it is largely unknown whether these isoforms encode proteins with distinct functions matching their expression pattern. In this report, we investigated the function and relationship of the two isoforms of Reep6, namely Reep6.1 and Reep6.2, in rod photoreceptor cells. These two isoforms result from the alternative splicing of exon 5 and show mutually exclusive expression patterns. Reep6.2 is the canonical isoform that is expressed in non-retinal tissues, whereas Reep6.1 is the only expressed isoform in the adult retina. The Reep6.1 isoform-specific knockout mouse, Reep6E5/E5, is generated by deleting exon 5 and a homozygous deletion phenotypically displayed a rod degeneration phenotype comparable to a Reep6 full knockout mouse, indicating that the Reep6.1 isoform is essential for the rod photoreceptor cell survival. Consistent with the results obtained from a loss-of-function experiment, overexpression of Reep6.2 failed to rescue the rod degeneration phenotype of Reep6 knockout mice whereas overexpression of Reep6.1 does lead to rescue. These results demonstrate that, consistent with the expression pattern of the isoform, Reep6.1 has rod-specific functions that cannot be substituted by its canonical isoform. Our findings suggested that a strict regulation of splicing is required for the maintenance of photoreceptor cells. Show less

Background Emergency cricothyrotomy is a critical, yet infrequently performed and time-sensitive procedure that requires practice in order to be reliably completed in emergent airway situations. Many physicians never have the opportunity to practice this rarely performed but highly impactful procedure during their training due to a lack of an affordable, high-fidelity training model. In this study, the educational impact and realism of a new synthetic cricothyrotomy training model… Show more

Background Emergency cricothyrotomy is a critical, yet infrequently performed and time-sensitive procedure that requires practice in order to be reliably completed in emergent airway situations. Many physicians never have the opportunity to practice this rarely performed but highly impactful procedure during their training due to a lack of an affordable, high-fidelity training model. In this study, the educational impact and realism of a new synthetic cricothyrotomy training model (high-fidelity emergency cricothyrotomy, HiFEC) were compared with those of a standard porcine explant model. Methodology A total of thirty-one attending physicians from four medical specialties were recruited on a volunteer basis to participate in a cricothyrotomy simulation workshop. Participants were randomly assigned to complete the initial workshop using one of the two models but had the opportunity to practice on both trainers. Pre- and post-workshop comfort level as well as the realism of the models were surveyed using questionnaires and evaluated using a five-point Likert scale. Results Improvements in self-reported comfort levels were seen in both the porcine group (p = 0.0014) and HiFEC group (p = 0.0036) as well as overall (p < 0.001). The realism rating of both training models was similar with a median score of 4 on a five-point Likert scale. When comparing the cost of conducting our workshop using these models, the synthetic model saved over $650. Conclusions Given the similar realism of the models and the improvement in participant comfort level, the synthetic HiFEC trainer is an effective and more affordable alternative training model for emergency cricothyrotomies. Show less

Ureteropelvic junction obstruction (UPJO) is an uncommonly encountered pathology, posing a challenge for resident training. We describe the development and face validation of a robotic pyeloplasty simulation using a 3D-printed silicone-based model of UPJO for surgical training, in combination with crowdsourced scoring to objectively assess performance and learning outcomes. The organs were created using 3D modeling software and printed using a silicone-based material by Lazarus 3D, LLC. They… Show more

Ureteropelvic junction obstruction (UPJO) is an uncommonly encountered pathology, posing a challenge for resident training. We describe the development and face validation of a robotic pyeloplasty simulation using a 3D-printed silicone-based model of UPJO for surgical training, in combination with crowdsourced scoring to objectively assess performance and learning outcomes. The organs were created using 3D modeling software and printed using a silicone-based material by Lazarus 3D, LLC. They were secured in a laparoscopic box trainer and the robotic system was docked. Eight residents and three faculty each performed two robotic-assisted right dismembered pyeloplasties on separate occaisions. Face validity was evaluated on a 5-point Likert scale. Crowd-Sourced Assessment of Technical Skills (C-SATS Inc.) scored surgical performance using the Global Evaluative Assessment of Robotic Skills (GEARS) criteria, based on video review of each simulation. All participants completed the simulation twice with fully patent anastomoses. Average time to complete the first and second trials was 44.4 min and 43.2 min, respectively. The average GEARS score was 17.1 and 17.6 for the first and second trials respectively. Participants improved on average in all 5 GEARS categories, with significant improvement in depth perception (p = 0.006). The model received mean scores (out of 5) of 4.36 for aesthetics, 4.18 for overall feel, 3.55 for realism, 4.72 for usability, and 4.72 for suturability. Residents had a significant increase in confidence between initial & final surveys on a 5-point Likert Scale: 1.63 vs. 2.38 (p = 0.03). Using 3D-printed silicone-based models, participants completed robotic-assisted dismembered pyeloplasties for training and skill acquisition. We demonstrated face validity of the simulation, which was also found to improve participant speed & significantly improve resident confidence. Crowdsourced assessment demonstrated significant improvement in depth perception. Show less

Hereditary retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding receptor expression-enhancing protein 6 (REEP6), in individuals with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a… Show more

Hereditary retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding receptor expression-enhancing protein 6 (REEP6), in individuals with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a frameshift mutation. In this study, we generated Reep6 compound heterozygous mice, Reep6L135P/−, which mimic the patient genotype and recapitulate the early-onset retinal degeneration phenotypes observed in the individual with RP. To determine the feasibility of rescuing the Reep6 mutant phenotype via gene replacement therapy, we delivered Reep6.1, the mouse retina-specific isoform of REEP6, to photoreceptors of Reep6 mutant mice on postnatal day 20. Evaluation of the therapeutic effects 2 months posttreatment showed improvements in the photoresponse as well as preservation of photoreceptor cells. Importantly, guanylyl cyclase 1 (GC1) expression was also restored to the outer segment after treatment. Furthermore, rAAV8-Reep6.1 single treatment in Reep6 mutant mice 1 year postinjection showed significant improvements in retinal function and morphology, suggesting that the treatment is effective even after a prolonged period. Findings from this study show that gene replacement therapy in the retina with rAAV overexpressing Reep6 is effective, preserving photoreceptor function in Reep6 mutant mice. These findings provide evidence that rAAV8-based gene therapy can prolong survival of photoreceptors in vivo and can be potentially used as a therapeutic modality for treatment of patients with RP. Show less

Introduction: We have reported the clinical benefits of fetal minimally invasive surgery (MIS) in attenuating preterm labor, uterine morbidity, and subsequent C-sections– complications associated with open fetal surgery. Other non-lethal diseases may also benefit from fetal MIS, such as gastroschisis. 3D printing allows the creation of lifelike human models. The aim of this study is developing & validating a 3D fetal MIS model to test an in utero procedure for gastroschisis repair.
Methods:… Show more

Introduction: We have reported the clinical benefits of fetal minimally invasive surgery (MIS) in attenuating preterm labor, uterine morbidity, and subsequent C-sections– complications associated with open fetal surgery. Other non-lethal diseases may also benefit from fetal MIS, such as gastroschisis. 3D printing allows the creation of lifelike human models. The aim of this study is developing & validating a 3D fetal MIS model to test an in utero procedure for gastroschisis repair.
Methods: A 3D reconstruction of a uterus & fetus with gastroschisis (based on a mid-gestation fetal MRI) was optimized & rapidly prototyped using a next-gen Lazarus 3D printer. A four-step MIS procedure (evaluation of fetus, evaluation of bowel, reduction of bowel, coverage of defect) was designed and time-tested in three cohorts repeated in triplicate (fetal/neonatal surgeons, residents, and students, n=6/group). A ten question post-trial validation survey was administered to the participants.
Results: All procedures were completed successfully (n=54). Operative time was significantly related to surgical training level (fetal/neonatal surgeons 125s+/-29s, residents 141s+/-30s, students 376s+/-107s; p<0.05) with sequential attempts yielding significant rates of improvement in all cohorts. All surgeons reported that the model 1) is an accurate tactile and visually representative model, 2) adequately assessed technical skills required for the procedure, & 3) would be a valuable training tool. The cost for this model was $68.69/trial and can be refurbished/reused for $200.
Conclusion:Our data supports construct, content, & face validity of a novel 3D fetal surgical simulator. This model is more cost effective than animal models in developing fetal techniques and seems to be more representative of the human disease. With the attenuation of maternal-fetal risk observed in fetal MIS, in utero therapies for gastroschisis may be considered.
Show less

NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1) encodes a rate-limiting enzyme that catalyzes the biosynthesis of NAD+ and plays a role in neuroprotection. Mutations in NMNAT1 have been identified to cause a recessive, non-syndromic early form of blindness genetically defined as Leber Congenital Amaurosis 9 (LCA9). One of the most common alleles reported so far in NMNAT1 is the c.769G > A (E257K) missense mutation, which occurs in 70% of all LCA9 cases. However, given its… Show more

NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1) encodes a rate-limiting enzyme that catalyzes the biosynthesis of NAD+ and plays a role in neuroprotection. Mutations in NMNAT1 have been identified to cause a recessive, non-syndromic early form of blindness genetically defined as Leber Congenital Amaurosis 9 (LCA9). One of the most common alleles reported so far in NMNAT1 is the c.769G > A (E257K) missense mutation, which occurs in 70% of all LCA9 cases. However, given its relatively high population frequency and the observation of individuals with homozygous E257K variant without phenotype, the pathogenicity of this allele has been questioned. To address this issue, we have studied the pathogenic effects of this allele by generating a knock-in mouse model. Interestingly, no obvious morphological or functional defects are observed in Nmnat1 E257K homozygous mice up to one year old, even after light-damage. Together with the previous clinical reports, we propose that the E257K allele is a weak hypomorphic allele that has significantly reduced penetrance in the homozygous state. In contrast, compound heterozygous Nmnat1E257K/- mice exhibit photoreceptor defects which are exacerbated upon exposure to light. Furthermore, retina tissue- specific Nmnat1 conditional knockout mice exhibit photoreceptor degeneration before the retina has terminally differentiated. These findings suggest that NMNAT1 plays an important role in photoreceptors and is likely involved in both retinal development and maintenance of photoreceptor integrity. Show less

Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families… Show more

Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases. Show less

The mammalian retina consists of multiple cell layers including photoreceptor cells, which are light sensing neurons that play essential functions in the visual process. Previously, we identified mutations in SPATA7, encoding spermatogenesis associated protein 7, in families with Leber Congenital Amaurosis (LCA) and juvenile Retinitis Pigmentosa (RP), and showed that Spata7 null mice recapitulate the human disease phenotype of retinal degeneration. SPATA7 is expressed in the connecting cilium… Show more

The mammalian retina consists of multiple cell layers including photoreceptor cells, which are light sensing neurons that play essential functions in the visual process. Previously, we identified mutations in SPATA7, encoding spermatogenesis associated protein 7, in families with Leber Congenital Amaurosis (LCA) and juvenile Retinitis Pigmentosa (RP), and showed that Spata7 null mice recapitulate the human disease phenotype of retinal degeneration. SPATA7 is expressed in the connecting cilium of photoreceptor (PR) cells in the mouse retina, as well as in retinal pigment epithelium (RPE) cells, but the functional role of Spata7 in the RPE remains unknown. To investigate whether Spata7 is required in PRs, the RPE, or both, we conditionally knocked out Spata7 in photoreceptors and RPE cells using Crx-Cre and Best1-Cre transgenic mouse lines, respectively. In Spata7 photoreceptor-specific conditional (cKO) mice, both rod and cone photoreceptor dysfunction and degeneration is observed, characterized by progressive thinning of the outer nuclear layer and reduced response to light; however, RPE-specific deletion of Spata7 does not impair retinal function or cell survival. Furthermore, our findings show that both Rhodopsin and RPGRIP1 are mislocalized in the Spata7Flox/-; Crx-Cre cKO mice, suggesting that loss of Spata7 in photoreceptors alone can result in altered trafficking of these proteins in the connecting cilium. Together, our findings suggest that loss of Spata7 in photoreceptors alone is sufficient to cause photoreceptor degeneration, but its function in the RPE is not required for photoreceptor survival; therefore, loss of Spata7 in photoreceptors alters both rod and cone function and survival, consistent with the clinical phenotypes observed in LCA and RP patients with mutations in SPATA7. Show less