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1.
Nat Biomed Eng ; 2023 Dec 05.
Article in English | MEDLINE | ID: mdl-38052996

ABSTRACT

Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation of a nylon catheter can be used to create a subcutaneous cavity that supports the transplantation and optimal function of a geometrically matching islet-encapsulation device consisting of a twisted nylon surgical thread coated with an islet-seeded alginate hydrogel. The neovascularized cavity led to the sustained reversal of diabetes, as we show in immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, owing to increased oxygenation, physiological glucose responsiveness and islet survival, as indicated by a computational model of mass transport. The cavity also allowed for the in situ replacement of impaired devices, with prompt return to normoglycemia. Controlled inflammation-induced neovascularization is a scalable approach, as we show with a minipig model, and may facilitate the clinical translation of immunosuppression-free subcutaneous islet transplantation.

2.
BMC Vet Res ; 18(1): 233, 2022 Jun 20.
Article in English | MEDLINE | ID: mdl-35718776

ABSTRACT

BACKGROUND: Canine intrarenal cystic lesions (ICLs) are infrequently reported in the veterinary literature. Several treatment options have been described including cyst fenestration (partial nephrectomy/deroofing) +/- omentalization, sclerotherapy using alcohol as a sclerosing agent, percutaneous cyst drainage (PCD), and ureteronephrectomy. Information regarding presenting clinical signs, physical examination findings, histologic diagnosis and outcomes of dogs with ICLs treated by different methods is limited. Medical records of 11 institutions were retrospectively reviewed to identify dogs that underwent PCD, sclerotherapy, surgical deroofing +/- omentalization, or ureteronephrectomy for management of ICLs from 2004 to 2021. Six weeks postoperative/post-procedural follow-up was required. Cases suspected to represent malignancy on preoperative imaging were excluded. The study objective was to provide information regarding perioperative characteristics, complications, and outcomes of dogs undergoing treatment of ICLs. RESULTS: Eighteen dogs were included, with 24 ICLs treated. Ten had bilateral. There were 15 males and 3 females, with crossbreeds predominating. PCD, sclerotherapy, deroofing and ureteronephrectomy were performed in 5 (5 ICLs treated), 7 (11 ICLs), 6 (6), and 7 (7) dogs, respectively, with 5 dogs undergoing > 1 treatment. Seven dogs experienced 8 complications, with requirement for additional intervention commonest. PCD, sclerotherapy and deroofing resulted in ICL resolution in 0/5, 3/11 and 3/6 treated ICLs, respectively. Histopathology identified renal cysts (RCs) in 7/13 dogs with histopathology available and neoplasia in 6/13 (4 malignant, 2 benign). Of 5 dogs diagnosed histopathologically with neoplasia, cytology of cystic fluid failed to identify neoplastic cells. Among 7 dogs with histologically confirmed RCs, 4 had concurrent ICLs in ipsilateral/contralateral kidney, compared with 2/6 dogs with histologically confirmed neoplasia. CONCLUSIONS: Benign and neoplastic ICLs were approximately equally common and cystic fluid cytology failed to differentiate the 2. Among renal-sparing treatments, deroofing most commonly resulted in ICL resolution. Presence of concurrent ICLs in ipsilateral/contralateral kidney does not appear reliable in differentiating benign from malignant ICLs.


Subject(s)
Cysts , Dog Diseases , Animals , Cysts/veterinary , Dog Diseases/drug therapy , Dog Diseases/surgery , Dogs , Ethanol , Female , Male , Retrospective Studies , Sclerosing Solutions/therapeutic use , Sclerotherapy/methods , Sclerotherapy/veterinary
3.
Vet Surg ; 51 Suppl 1: O167-O173, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35199354

ABSTRACT

OBJECTIVE: To describe a minimally invasive approach to the parathyroid gland for the treatment of primary hyperparathyroidism. STUDY DESIGN: Surgical technique description and clinical case report. ANIMALS: Five canine cadavers and 5 client-owned dogs with primary hyperparathyroidism. METHODS: A surgical technique for minimally invasive video-assisted parathyroidectomy (MIVAP), described for humans, was adapted for dogs. With the dog in dorsal recumbency, a 15 mm incision was made on the midline, 1 finger width caudal to the cricoid cartilage of the larynx. A 5 mm 30° rigid endoscope was inserted into the peritracheal space with the aid of a blunt suction dissector, and fine elevators. The parathyroid was subsequently removed using electrocautery and blunt and sharp dissection. The technique was refined in 5 cadaver dogs to assess feasibility, and was subsequently performed in 5 clinical cases. RESULTS: A minimally invasive approach to the parathyroid gland was possible and allowed successful removal of a parathyroid mass in 5 dogs without complication. The use of fluid ingress was trialed in 1 cadaver and not found to be helpful. The use of a blunt suction dissector greatly facilitated dissection of the peritracheal space. CONCLUSION: Minimally invasive video-assisted parathyroidectomy is feasible in dogs and was not associated with complications in 5 clinical cases. CLINICAL SIGNIFICANCE: Minimally invasive techniques tend to reduce morbidity and are popular with pet owners. This study demonstrates that a minimally invasive technique may be considered for parathyroidectomy in dogs.


Subject(s)
Dog Diseases , Hyperparathyroidism, Primary , Animals , Cadaver , Dog Diseases/surgery , Dogs , Feasibility Studies , Humans , Hyperparathyroidism, Primary/surgery , Hyperparathyroidism, Primary/veterinary , Minimally Invasive Surgical Procedures/veterinary , Parathyroidectomy/veterinary , Video-Assisted Surgery/methods , Video-Assisted Surgery/veterinary
4.
Small ; 18(8): e2104899, 2022 02.
Article in English | MEDLINE | ID: mdl-34897997

ABSTRACT

Encapsulation and transplantation of insulin-producing cells offer a promising curative treatment for type 1 diabetes (T1D) without immunosuppression. However, biomaterials used to encapsulate cells often elicit foreign body responses, leading to cellular overgrowth and deposition of fibrotic tissue, which in turn diminishes mass transfer to and from transplanted cells. Meanwhile, the encapsulation device must be safe, scalable, and ideally retrievable to meet clinical requirements. Here, a durable and safe nanofibrous device coated with a thin and uniform, fibrosis-mitigating, zwitterionically modified alginate hydrogel for encapsulation of islets and stem cell-derived beta (SC-ß) cells is reported. The device with a configuration that has cells encapsulated within the cylindrical wall, allowing scale-up in both radial and longitudinal directions without sacrificing mass transfer, is designed. Due to its facile mass transfer and low level of fibrotic reactions, the device supports long-term cell engraftment, correcting diabetes in C57BL6/J mice with rat islets for up to 399 days and SCID-beige mice with human SC-ß cells for up to 238 days. The scalability and retrievability in dogs are further demonstrated. These results suggest the potential of this new device for cell therapies to treat T1D and other diseases.


Subject(s)
Diabetes Mellitus, Experimental , Insulins , Islets of Langerhans Transplantation , Animals , Diabetes Mellitus, Experimental/therapy , Dogs , Fibrosis , Islets of Langerhans Transplantation/methods , Mice , Mice, SCID , Rats
5.
J Am Vet Med Assoc ; 260(2): 212-227, 2022 01 14.
Article in English | MEDLINE | ID: mdl-34936575

ABSTRACT

OBJECTIVE: To characterize clinical features, comorbidities, frequency of bacterial isolation, and survival time in cats with suppurative cholangitis-cholangiohepatitis syndrome (S-CCHS). ANIMALS: 168 client-owned cats with S-CCHS. PROCEDURES: Data were prospectively (1980 to 2019) collected regarding clinical features, comorbidities, bacterial infection, illness duration, and treatments. Variables were evaluated for associations with survival time. RESULTS: Median age of cats was 10.0 years, with no breed or sex predilection observed. Common clinical features included hyporexia (82%), hyperbilirubinemia (80%), lethargy (80%), vomiting (80%), jaundice (67%), weight loss (54%), and hypoalbuminemia (50%). Comorbidities included extrahepatic bile duct obstruction (53%), cholelithiasis (42%), cholecystitis (40%), and ductal plate malformation (44%) as well as biopsy-confirmed inflammatory bowel disease (60/68 [88%]) and pancreatitis (41/44 [93%]). Bacterial cultures were commonly positive (69%) despite prebiopsy antimicrobial administration in most cats. Of surgically confirmed choleliths, diagnostic imaging identified only 58%. Among 55 cats with "idiopathic pancreatitis," 28 (51%) were documented to have transiting choleliths, and 20 had pancreatic biopsies confirming pancreatitis. Cholelithiasis (with or without bile duct obstruction) and cholecystectomy were associated with survival advantages. Survival disadvantages were found for leukocytosis, ≥ 2-fold increased alkaline phosphatase, and hyperbilirubinemia. Cholecystoenterostomy had no survival impact. Cats with ductal plate malformations were significantly younger at diagnosis and death than other cats. Chronic treatments with antimicrobials, S-adenosylmethionine, and ursodeoxycholic acid were common postbiopsy. CLINICAL RELEVANCE: S-CCHS in cats was associated with bacterial infection and various comorbidities and may be confused with pancreatitis. Surgically correctable morbidities (ie, cholecystitis, cholecystocholelithiasis) and cholecystectomy provided a significant survival advantage.


Subject(s)
Bacterial Infections , Cat Diseases , Cholangitis , Pancreatitis , Animals , Bacterial Infections/veterinary , Cats , Cholangitis/complications , Cholangitis/veterinary , Cholecystectomy/veterinary , Pancreatitis/diagnosis , Pancreatitis/veterinary , Vomiting/veterinary
6.
Am J Vet Res ; 83(1): 23-32, 2021 Nov 10.
Article in English | MEDLINE | ID: mdl-34757924

ABSTRACT

OBJECTIVE: To determine whether serum C-reactive protein (CRP) concentration could be used to detect gallbladder rupture (GBR) prior to surgery in dogs undergoing cholecystectomy for treatment of gallbladder mucocele (GBM). ANIMALS: 45 dogs that underwent cholecystectomy because of GBM at a companion animal referral hospital from 2017 to 2020. PROCEDURES: Electronic medical records were reviewed, and dogs were included if serum CRP concentration had been measured within 24 hours prior to cholecystectomy. Dogs were grouped as to whether the gallbladder was found to be ruptured or intact during surgery. Accuracy of using preoperative CRP concentration to predict GBR was compared with accuracy of abdominal ultrasonography and other preoperative blood tests. RESULTS: GBR was present in 15 dogs at the time of surgery. Median preoperative CRP concentration was significantly higher in dogs with GBR (15.1 mg/dL; interquartile range, 7.4 to 16.8 mg/dL) than in dogs with an intact gallbladder (2.65 mg/dL; interquartile range, 0.97 to 13.4 mg/dL). Sensitivity, specificity, and accuracy of using preoperative CRP concentration to predict GBR were 100%, 67%, and 78%, respectively. CLINICAL RELEVANCE: Measurement of preoperative CRP concentration provided excellent sensitivity and moderate specificity for detection of GBR in dogs undergoing cholecystectomy because of GBM. Accuracy of using preoperative CRP concentration for detection of GBR was not superior to the accuracy of preoperative abdominal ultrasonography. However, when CRP concentration was combined with results of ultrasonography, the sensitivity, specificity, and accuracy for detection of GBR were 100%, 93%, and 96%, respectively.


Subject(s)
Dog Diseases , Mucocele , Animals , C-Reactive Protein , Dog Diseases/diagnosis , Dog Diseases/surgery , Dogs , Gallbladder/surgery , Mucocele/diagnosis , Mucocele/surgery , Mucocele/veterinary , Ultrasonography/veterinary
7.
J Am Vet Med Assoc ; 259(9): 1009-1024, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34647474

ABSTRACT

OBJECTIVE: To characterize the association between peritoneopericardial diaphragmatic hernia (PPDH) or congenital central diaphragmatic hernia (CCDH) and ductal plate malformations (DPMs) in dogs and cats. ANIMALS: 18 dogs and 18 cats with PPDH or CCDH and 19 dogs and 18 cats without PPDH or CCDH. PROCEDURES: Evaluation of clinical details verified PPDH or CCDH and survival times. Histologic features of nonherniated liver samples were used to categorize DPM. Immunohistochemical staining for cytokeratin-19 distinguished bile duct profiles per portal tract and for Ki-67-assessed cholangiocyte proliferation. Histologic features of herniated liver samples from PPDH or CCDH were compared with those of pathological controls (traumatic diaphragmatic hernia, n = 6; liver lobe torsion, 6; ischemic hepatopathy, 2). RESULTS: DPM occurred in 13 of 18 dogs with the proliferative-like phenotype predominating and in 15 of 18 cats with evenly distributed proliferative-like and Caroli phenotypes. Congenital hepatic fibrosis DPM was noted in 3 dogs and 2 cats and renal DPM in 3 dogs and 3 cats. No signalment, clinical signs, or clinicopathologic features discriminated DPM. Kaplan Meier survival curves were similar in dogs and cats. Bile duct profiles per portal tract in dogs (median, 5.0; range, 1.4 to 100.8) and cats (6.6; 1.9 to 11.0) with congenital diaphragmatic hernias significantly exceeded those in healthy dogs (1.4; 1.2 to 1.6) and cats (2.3; 1.7 to 2.6). Animals with DPM lacked active cholangiocyte proliferation. Histologic features characterizing malformative bile duct profiles yet without biliary proliferation were preserved in herniated liver lobes in animals with DPM. CONCLUSIONS AND CLINICAL RELEVANCE: DPM was strongly associated with PPDH and CCDH. Because DPM can impact health, awareness of its coexistence with PPDH or CCDH should prompt biopsy of nonherniated liver tissue during surgical correction of PPDH and CCDH.


Subject(s)
Cat Diseases , Dog Diseases , Hernias, Diaphragmatic, Congenital , Animals , Cats , Dogs , Hernias, Diaphragmatic, Congenital/veterinary , Liver Cirrhosis/veterinary
8.
Adv Mater ; 33(39): e2102852, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34363254

ABSTRACT

Encapsulation of insulin-producing cells is a promising strategy for treatment of type 1 diabetes. However, engineering an encapsulation device that is both safe (i.e., no cell escape and no breakage) and functional (i.e., low foreign-body response (FBR) and high mass transfer) remains a challenge. Here, a family of zwitterionic polyurethanes (ZPU) with sulfobetaine groups in the polymer backbone is developed, which are fabricated into encapsulation devices with tunable nanoporous structures via electrospinning. The ZPU encapsulation device is hydrophilic and fouling-resistant, exhibits robust mechanical properties, and prevents cell escape while still allowing efficient mass transfer. The ZPU device also induces a much lower FBR or cellular overgrowth upon intraperitoneal implantation in C57BL/6 mice for up to 6 months compared to devices made of similar polyurethane without the zwitterionic modification. The therapeutic potential of the ZPU device is shown for islet encapsulation and diabetes correction in mice for ≈3 months is demonstrated. As a proof of concept, the scalability and retrievability of the ZPU device in pigs and dogs are further demonstrated. Collectively, these attributes make ZPU devices attractive candidates for cell encapsulation therapies.


Subject(s)
Biocompatible Materials/chemistry , Islets of Langerhans/chemistry , Nanopores , Polyurethanes/chemistry , Animals , Cell- and Tissue-Based Therapy , Diabetes Mellitus, Experimental/therapy , Dogs , Hydrophobic and Hydrophilic Interactions , Islets of Langerhans/physiology , Islets of Langerhans Transplantation/adverse effects , Male , Mice , Mice, Inbred C57BL , Swine
9.
J Am Vet Med Assoc ; 258(12): 1378-1385, 2021 Jun 15.
Article in English | MEDLINE | ID: mdl-34061615

ABSTRACT

OBJECTIVE: To quantify the relative risk of intestinal dehiscence in dogs undergoing intestinal resection and anastomosis (IRA), compared with enterotomy, for surgical management of small intestinal foreign bodies, and to evaluate the association between nasogastric tube placement for early enteral nutrition (EEN) and hospitalization time. ANIMALS: 211 dogs undergoing 227 surgeries for intestinal foreign body removal. PROCEDURES: Medical records were reviewed for dogs undergoing a single-site sutured enterotomy or IRA for foreign body intestinal obstruction between May 2008 and April 2018. Multivariable logistic regression was used to quantify the association between surgical procedure and dehiscence. Multiple linear regression was used to quantify the association of nasogastric tube placement with total hospitalization time. RESULTS: Dehiscence rates were 3.8% (7/183) and 18.2% (8/44) for enterotomy and IRA, respectively. Overall dehiscence rate for all surgeries was 6.6% (15/227). The odds of intestinal dehiscence for IRA were 6.09 times (95% CI, 1.89 to 19.58) the odds for enterotomy. An American Society of Anesthesiologists score > 3 (OR, 4.49; 95% CI, 1.43 to 14.11) and an older age (OR, 1.02 [95% CI, 1.01 to 1.02] for each 1-month increase in age) were significantly associated with greater odds of intestinal dehiscence, regardless of surgical procedure. Placement of a nasogastric tube was not associated with intestinal dehiscence or decreased total hospitalization time when controlling for the year of surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Patients undergoing IRA were at a significantly higher risk of intestinal dehiscence, compared with patients undergoing enterotomy. Although this finding should not be used to recommend enterotomy over IRA, this information may be useful in guiding owner expectations and postoperative monitoring.


Subject(s)
Digestive System Surgical Procedures , Dog Diseases , Foreign Bodies , Anastomosis, Surgical/veterinary , Animals , Digestive System Surgical Procedures/veterinary , Dog Diseases/surgery , Dogs , Foreign Bodies/surgery , Foreign Bodies/veterinary , Retrospective Studies , Surgical Wound Dehiscence/veterinary
10.
Sci Transl Med ; 13(596)2021 06 02.
Article in English | MEDLINE | ID: mdl-34078744

ABSTRACT

Transplantation of stem cell-derived ß (SC-ß) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining maximum mass transfer and decreased cellular overgrowth on blank (cell-free) devices to as low as a single-cell layer (~3 micrometers thick) when implanted in the peritoneal cavity of mice. We confirmed device safety, indicated as continuous containment of proliferative cells within the device for 5 months. Encapsulating syngeneic, allogeneic, or xenogeneic rodent islets within the device corrected chemically induced diabetes in mice and cells remained functional for up to 200 days. The function of human SC-ß cells was supported by the device, and it reversed diabetes within 1 week of implantation in immunodeficient and immunocompetent mice, for up to 120 and 60 days, respectively. We demonstrated the scalability and retrievability of the device in dogs and observed viable human SC-ß cells despite xenogeneic immune responses. The nanofibrous device design may therefore provide a translatable solution to the balance between safety and functionality in developing stem cell-based therapies for T1D.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Insulin-Secreting Cells , Insulins , Islets of Langerhans Transplantation , Nanofibers , Animals , Diabetes Mellitus, Experimental/therapy , Diabetes Mellitus, Type 1/therapy , Dogs , Insulin , Mice
11.
Sci Adv ; 7(20)2021 05.
Article in English | MEDLINE | ID: mdl-33990318

ABSTRACT

Cell encapsulation represents a promising therapeutic strategy for many hormone-deficient diseases such as type 1 diabetes (T1D). However, adequate oxygenation of the encapsulated cells remains a challenge, especially in the poorly oxygenated subcutaneous site. Here, we present an encapsulation system that generates oxygen (O2) for the cells from their own waste product, carbon dioxide (CO2), in a self-regulated (i.e., "inverse breathing") way. We leveraged a gas-solid (CO2-lithium peroxide) reaction that was completely separated from the aqueous cellular environment by a gas permeable membrane. O2 measurements and imaging validated CO2-responsive O2 release, which improved cell survival in hypoxic conditions. Simulation-guided optimization yielded a device that restored normoglycemia of immunocompetent diabetic mice for over 3 months. Furthermore, functional islets were observed in scaled-up device implants in minipigs retrieved after 2 months. This inverse breathing device provides a potential system to support long-term cell function in the clinically attractive subcutaneous site.

12.
Vet Surg ; 49(2): 321-328, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31664719

ABSTRACT

OBJECTIVE: To compare the effect of three methods of subcutaneous tissue closure on postoperative incisional complications and pain in cats. STUDY DESIGN: Single-center, randomized, blinded, controlled trial conducted in a veterinary teaching hospital. ANIMALS: Two hundred ninety-seven cats undergoing midline celiotomy for ovariohysterectomy (n = 280) or other abdominal procedure (n = 17). METHODS: Cats (n = 297) were assigned to one of three subcutaneous closure methods: simple continuous apposition with tacking to the rectus fascia (n = 108, quilting [Q] group); simple continuous apposition (SC; n = 94); no subcutaneous closure (NC; n = 95). Primary outcomes were incidence of seroma formation, postoperative pain, and surgical site infection or dehiscence. Active follow-up was obtained at 10 and 30 days postoperatively. RESULTS: Baseline characteristics did not differ between groups. Seroma was less common in the Q group (13.0%) than in the NC (27.3%) and SC (25.9%) groups (P = .03). Compared with the other two groups, the relative risk of seroma formation in the Q group was 0.49 (95% CI = 0.28-0.86, P = .01). Median mechanical pain thresholds were higher (indicating greater comfort) in cats with subcutaneous sutures (Q and SC = 1.23 [interquartile range (IQR), 0.2-2.6 N], NC = 0.83 [IQR, 0-1.87 N], P = .04) on the day after surgery. CONCLUSION: Closing subcutaneous tissues with a quilting closure pattern reduced seroma formation in cats undergoing celiotomy. CLINICAL SIGNIFICANCE: Placing a quilting suture pattern in the subcutaneous tissues after celiotomy is a simple low-cost measure that reduces seromas in cats. Abstaining from subcutaneous closure cannot be recommended because of increased seroma formation and pain.


Subject(s)
Pain, Postoperative/veterinary , Postoperative Complications/veterinary , Suture Techniques/veterinary , Sutures , Wound Closure Techniques/veterinary , Abdomen , Animals , Cats , Female , Laparotomy/adverse effects , Pain, Postoperative/prevention & control , Postoperative Complications/etiology , Plastic Surgery Procedures/veterinary , Seroma/etiology , Seroma/veterinary , Surgical Wound Infection/prevention & control , Surgical Wound Infection/veterinary , Suture Techniques/adverse effects , Sutures/adverse effects
13.
Vet Surg ; 49(2): 265-273, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31598999

ABSTRACT

OBJECTIVE: To report the clinical characteristics, types of vascular ring anomalies (VRA), operative findings, complications, and survival after surgical treatment of cats with VRA. STUDY DESIGN: Retrospective, multi-institutional case series. ANIMALS: Client- or shelter-owned cats presenting to academic, referral veterinary institutions. METHODS: Medical records of cats with VRA that underwent surgical treatment were reviewed. Signalment, relevant medical history, clinical signs, diagnostic imaging, surgical findings, complications, and survival were recorded. RESULTS: Twenty cats with VRA were included. Vascular ring anomalies were most commonly (75% [15/20]) diagnosed in cats less than 1 year old, with no breed or sex predilection. Regurgitation was the most common clinical sign, present in 18 of 20 (90%) cats. A persistent right aortic arch was diagnosed in 17 of 20 (85%) cats, with concurrent aberrant left subclavian artery in four of the cats. Surgical treatment was associated with survival to discharge in 18 of 20 (90%) cats. Persistent clinical signs were reported in nine of 13 (69%) cats, and radiographic evidence of megaesophagus persisted in four of 13 (31%) cats, with a median follow-up of 275 days after discharge. CONCLUSION: Persistent right aortic arch was the most commonly diagnosed VRA in cats in this series, although multiple anomalies were observed. Surgical treatment of VRA in cats was associated with a high survival to discharge, although persistence of clinical signs and megaesophagus was noted in 69% and 31% of the cats, respectively. CLINICAL SIGNIFICANCE: Surgical treatment of VRA in cats is associated with a high survival rate; however, persistence of clinical signs is an expected outcome.


Subject(s)
Cardiovascular Abnormalities/veterinary , Cat Diseases/pathology , Subclavian Artery/abnormalities , Vascular Ring/veterinary , Abnormalities, Multiple , Animals , Cardiovascular Abnormalities/pathology , Cats , Female , Male , Retrospective Studies , Subclavian Artery/pathology , Vascular Ring/pathology , Vascular Ring/surgery
14.
Adv Mater ; 31(52): e1905135, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31709667

ABSTRACT

Cell replacement therapy is emerging as a promising treatment platform for many endocrine disorders and hormone deficiency diseases. The survival of cells within delivery devices is, however, often limited due to low oxygen levels in common transplantation sites. Additionally, replacing implanted devices at the end of the graft lifetime is often unfeasible and, where possible, generally requires invasive surgical procedures. Here, the design and testing of a modular transcutaneous biphasic (BP) cell delivery device that provides enhanced and unlimited oxygen supply by direct contact with the atmosphere is presented. Critically, the cell delivery unit is demountable from the fixed components of the device, allowing for surgery-free refilling of the therapeutic cells. Mass transfer studies show significantly improved performance of the BP device in comparison to subcutaneous controls. The device is also tested for islet encapsulation in an immunocompetent diabetes rodent model. Robust cell survival and diabetes correction is observed following a rat-to-mouse xenograft. Lastly, nonsurgical cell refilling is demonstrated in dogs. These studies show the feasibility of this novel device for cell replacement therapies.


Subject(s)
Cell- and Tissue-Based Therapy/instrumentation , Membranes, Artificial , Animals , Cell Line , Cell- and Tissue-Based Therapy/methods , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/therapy , Hydrocarbons/chemistry , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/transplantation , Mice , Mice, Inbred C57BL , Nanostructures/chemistry , Oxygen/metabolism , Polymers/chemistry , Polytetrafluoroethylene/chemistry , Rats , Rats, Sprague-Dawley , Titanium/chemistry
15.
Nat Commun ; 10(1): 5262, 2019 11 20.
Article in English | MEDLINE | ID: mdl-31748525

ABSTRACT

Foreign body reaction (FBR) to implanted biomaterials and medical devices is common and can compromise the function of implants or cause complications. For example, in cell encapsulation, cellular overgrowth (CO) and fibrosis around the cellular constructs can reduce the mass transfer of oxygen, nutrients and metabolic wastes, undermining cell function and leading to transplant failure. Therefore, materials that mitigate FBR or CO will have broad applications in biomedicine. Here we report a group of zwitterionic, sulfobetaine (SB) and carboxybetaine (CB) modifications of alginates that reproducibly mitigate the CO of implanted alginate microcapsules in mice, dogs and pigs. Using the modified alginates (SB-alginates), we also demonstrate improved outcome of islet encapsulation in a chemically-induced diabetic mouse model. These zwitterion-modified alginates may contribute to the development of cell encapsulation therapies for type 1 diabetes and other hormone-deficient diseases.


Subject(s)
Alginates/chemistry , Betaine/analogs & derivatives , Cell Encapsulation/methods , Diabetes Mellitus, Type 1/therapy , Foreign-Body Reaction/prevention & control , Animals , Betaine/chemistry , Carbonic Acid , Cell Proliferation , Diabetes Mellitus, Experimental , Dogs , Fibrosis , Islets of Langerhans Transplantation/methods , Mice , Rats , Swine
16.
Nat Commun ; 10(1): 4602, 2019 10 10.
Article in English | MEDLINE | ID: mdl-31601796

ABSTRACT

The success of engineered cell or tissue implants is dependent on vascular regeneration to meet adequate metabolic requirements. However, development of a broadly applicable strategy for stable and functional vascularization has remained challenging. We report here highly organized and resilient microvascular meshes fabricated through a controllable anchored self-assembly method. The microvascular meshes are scalable to centimeters, almost free of defects and transferrable to diverse substrates, ready for transplantation. They promote formation of functional blood vessels, with a density as high as ~220 vessels mm-2, in the poorly vascularized subcutaneous space of SCID-Beige mice. We further demonstrate the feasibility of fabricating microvascular meshes from human induced pluripotent stem cell-derived endothelial cells, opening a way to engineer patient-specific microvasculature. As a proof-of-concept for type 1 diabetes treatment, we combine microvascular meshes and subcutaneously transplanted rat islets and achieve correction of chemically induced diabetes in SCID-Beige mice for 3 months.


Subject(s)
Cell Culture Techniques/instrumentation , Diabetes Mellitus, Experimental/therapy , Islets of Langerhans Transplantation/methods , Microvessels/growth & development , Animals , Bioengineering , Cell Culture Techniques/methods , Diabetes Mellitus, Experimental/complications , Female , Human Umbilical Vein Endothelial Cells , Humans , Hyperglycemia/therapy , Induced Pluripotent Stem Cells/cytology , Islets of Langerhans Transplantation/instrumentation , Male , Mice, SCID , Microvessels/cytology , Microvessels/physiology , Neovascularization, Physiologic , Rats, Sprague-Dawley
17.
Vet Surg ; 48(5): 803-819, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31111521

ABSTRACT

OBJECTIVE: To report intraoperative and major postoperative complications in dogs treated surgically for epiglottic retroversion (ER), compare the incidence of major postoperative complications between procedures, and report survival of surgically treated dogs. STUDY DESIGN: Multi-institutional retrospective study. SAMPLE POPULATION: Fifty dogs treated with 78 procedures. METHODS: Medical records of dogs diagnosed and surgically treated for ER from 2003 to 2017 at 11 institutions were reviewed. Complications were divided into intraoperative and major postoperative complications. RESULTS: Intraoperative complications occurred during 2 of 78 (2.6%) procedures. Thirty-six major postoperative complications were documented in 22 dogs after 36 of 74 (48.7%) procedures. Postoperative complications occurred after 7 of 12 (58.3%) nonincisional epiglottopexy, 23 of 43 (53.5%) incisional epiglottopexy, 2 of 4 (50%) partial epiglottectomy, 2 of 12 (16.7%) subtotal epiglottectomy, and 2 of 3 (66.7%) other surgical procedures. Epiglottopexy failure was the most common major postoperative complication. The incidence of major postoperative complications did not differ between procedures (P = .1239), although, when combined, epiglottopexy procedures (30/55) had a higher incidence of complications than epiglottectomy procedures (4/16; P = .048). Thirty (60%) dogs were alive at a median of 928 days (range, 114-2805), 8 (16%) were lost to follow-up after 411 days (range, 43-1158), and 12 (24%) were dead/euthanized after 301.5 days (range, 3-1212). Median survival time was not reached after a median of 716 days. CONCLUSION: Although intraoperative complications were uncommon, major postoperative complications were common, especially after epiglottopexy procedures. CLINICAL SIGNIFICANCE: Although surgical treatment of ER is associated with a high rate of major postoperative complications, especially epiglottopexy procedures, long-term survival can be achieved.


Subject(s)
Dog Diseases/surgery , Intraoperative Complications/veterinary , Laryngeal Diseases/veterinary , Postoperative Complications/veterinary , Animals , Dogs , Epiglottis , Female , Laryngeal Diseases/surgery , Male , Postoperative Period , Retrospective Studies , Treatment Outcome
18.
Vet Surg ; 47(2): 204-211, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29205404

ABSTRACT

OBJECTIVE: To determine the influence of a quilting suture pattern tacking the subcutaneous tissues to the deep fascia on complications after midline celiotomy in dogs. STUDY DESIGN: Single-center, randomized, blinded, controlled trial conducted in a veterinary teaching hospital. ANIMALS: Four hundred thirty-two dogs undergoing midline celiotomy for ovariohysterectomy (n = 249) or other abdominal procedures (n = 183). METHODS: Dogs were randomly assigned to (1) a quilting group, subcutaneous tissue with apposition plus tacking to the rectus fascia or (2) a nonquilting group, with apposition of subcutaneous tissue without tacking. Randomization was stratified on hospital admitting service. Primary outcome was the incidence of incisional seroma. Secondary outcomes included postoperative pain the day after surgery and surgical site infection (SSI). Outcomes were assessed during the first 30 postoperative days. RESULTS: No differences were detected between the quilting group (n = 183) and the nonquilting group (n = 175) in terms of illness severity, surgical procedure performed, surgeon's experience, duration of surgery, intraoperative complications, or methods of surgical closure other than the intervention under study. In an intent-to-treat analysis, the incidence of incisional seroma was lower in the quilting group (odds ratio = 0.30, 95% CI = 0.13-0.67, P = .004). Pain assessed 24 hours postoperatively was lower in the quilting group (P = .03). The incidence of SSI did not differ between groups. CONCLUSION: Tacking the subcutaneous tissues to the deep fascia is indicated to reduce seroma during celiotomy closure.


Subject(s)
Abdominal Muscles/surgery , Dogs/surgery , Laparotomy/veterinary , Seroma/veterinary , Suture Techniques/veterinary , Animals , Double-Blind Method , Female , Laparotomy/instrumentation , Pain, Postoperative/prevention & control , Pain, Postoperative/veterinary , Postoperative Complications/prevention & control , Postoperative Complications/veterinary , Seroma/prevention & control , Treatment Outcome
19.
Proc Natl Acad Sci U S A ; 115(2): E263-E272, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29279393

ABSTRACT

Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here, we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1-mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential.


Subject(s)
Cell- and Tissue-Based Therapy , Islets of Langerhans Transplantation/methods , Islets of Langerhans/physiology , Alginates , Animals , Diabetes Mellitus, Experimental/therapy , Dimethylformamide , Dogs , Glucuronic Acid , Hexuronic Acids , Humans , Hydrogels , Mice , Mice, SCID , Polymethyl Methacrylate , Rats
20.
Vet Radiol Ultrasound ; 59(2): 169-179, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29194832

ABSTRACT

The mediastinal serous cavity is a normal anatomic space in the caudal mediastinum. Aims of this anatomic and case series study were to describe the signs of pathologic expansion of the mediastinal serous cavity observed during computed tomography (CT), review the underlying anatomy, perform a literature review, and evaluate the medical records of several dogs with mediastinal serous cavity empyema (paraesophageal empyema). The mesothelial lined mediastinal serous cavity is a cranial extension of the omental bursa, separated from the peritoneal cavity by the diaphragm, in the dorsal part of the caudal mediastinum, to the right of the esophagus, between the heart base and diaphragm. In five adult, large-breed dogs with surgically and histologically confirmed paraesophageal empyema, macroscopic plant material was found at surgery in two dogs, adherence to adjacent lung was present in three different dogs, accessory lobectomy was performed in two dogs with subacute-chronic pyogranulomatous pneumonia, and one dog had concurrent pyothorax and mediastinitis, but none had esophageal abnormalities. This study expands our understanding of the pathogenesis and basis for the imaging appearance of paraesophageal empyema in dogs by clarifying the underlying anatomic structures that direct development of this condition. The term empyema accurately describes this condition because the purulent material accumulates within an existing body cavity. The study also provides initial evidence that the development of paraesophageal empyema might be due to local extension of lung disease, such as foreign body migration or pneumonia. Computed tomography was helpful for diagnosis, assessing size, and determining the spread of disease.


Subject(s)
Dog Diseases/etiology , Empyema/veterinary , Esophageal Diseases/veterinary , Radiography, Thoracic/veterinary , Tomography, X-Ray Computed/veterinary , Animals , Dog Diseases/diagnostic imaging , Dogs , Empyema/diagnostic imaging , Empyema/etiology , Esophageal Diseases/diagnostic imaging , Esophageal Diseases/etiology , Female , Male , Mediastinum/pathology , Serous Membrane/pathology
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