WO2021076716A1 - Additive manufacturing of personalized absorbable stents - Google Patents

Abstract

A personalized, bioresorbable, polymeric stent for placement in a body conduit, methods of making personalized, bioresorbable, polymeric stents for placement in a body conduit, and methods of repairing body conduits.

Description

ADDITIVE MANUFACTURING OF PERSONALIZED ABSORBABLE STENTS PRIORITY

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/915,275, filed October 15, 2019, which is incorporated by reference herein in its entirety.

GOVERNMENT FUNDING

[0002] This invention was made with government support under Grant Number T32EB019944 awarded by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] Small bowel perforations and obstructions are relatively frequent surgical emergencies, are potentially life-threatening, and have multiple etiologies. In general, treatment requires urgent surgical repair or resection and at times can lead to further complications. Stents may be used to help with healing intestinal perforations but their use is limited as currently available stents are non-absorbable, are manufactured in a narrow size range, and/or are limited to usage in locations that are accessible for endoscopic removal post-healing. Compositions and methods are needed in the art to provide personalized, bioresorbable, polymeric stent for placement in a body conduits such as the small intestine.

SUMMARY

[0004] In an embodiment, a personalized, bioresorbable, polymeric stent for placement in a body conduit is provided. A stent can be made up of polymer comprising one or more of glycolic acid, lactic acid, 1 ,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, e-caprolactone; polyglycolic acid; polylactic acid; polydioxanone; polycaprolactone; poly(lactide-co-caprolactone); poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoates; polyester; polycarbonate; tyrosine polycarbonate; polyamide; polypeptide; poly(amino acid); polyester; polyesteramide; poly(alkylene alkylate); polyether; polyethylene glycol; polyvinyl pyrrolidone; polyurethane; polyetherester; polyacetal; polycyanoacrylate; poly(oxyethylene)/polyoxypropylene) copolymer; polyacetal; polyketal; polyphosphate; polyphosphoester; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid); silk; chitin; chitosan; polysaccharide; and poly-4- hydroxybutyrate. A stent can be made up of a polymer comprising polydioxanone and polycaprolactone. A stent can be made of, for example, polydioxanone and polycaprolactone in a ratio of about 10:90, 20:80, 25:75; 30:70, 40:60, 50:50; or 75:25. A stent can be in the shape of a cylinder with a central bore. A stent can have a thickness of about 0.5, 0.75, 1.0, 1 .25, 1.5 mm or more. A stent can be about 0.1 , 0.5, 1.0, 2.5, 5, 0, 7.5, 10, 15, 20, 25, 30, 40, 45, 50, 60, 70, 80, 100 mm or more in length. In some embodiments, the inner diameter of the stent can be about 1.0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 5,0, 6.0, 7,0, 8.0, 9.0, 10.0 cm or more. In some embodiments, the inner diameter of the stent can be about 1.75 to about 3.5 cm. A stent can have 2, 3, 4, 5, 6, 7, 8, 10 or more suture holes at, for example, each end or at any other position along the stent. The outer diameter of the stent can be larger at the ends of the cylinder as compared to the outer diameter at the middle of the stent. The outer diameter of the stent at the ends of the stent can be about 0.1 , 0.5, 0.75, 1.0, 1.25 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.75, 4.0 or more mm larger than the outer diameter of the stent at the middle of the stent. The thicknesses of the ends of the cylinder can be greater than that of the thickness of the remainder of the cylinder forming thickened rims at each end of the cylinder. The rims of the cylinder can be about 0.1 , 0.25, 0.5, 0.75, 1.0 mm or more thicker than the remainder of the cylinder. The stent can be 3D printed.

[0005] An embodiment provides a method of making a personalized, bioresorbable, polymeric stent for a particular subject. The method can include: (a) imaging a body conduit of the subject to form an image of the body conduit; (b) determining a maximum body conduit diameter from the image; (c) using computer aided design to produce a body conduit design using the maximum body conduit diameter or a larger diameter; and (d) making the personalized, bioresorbable, polymeric stent using 3D printing. The personalized, bioresorbable, polymeric stent can have a diameter of about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.25, 1 .5, 1.75, 2.0, 3.0, 4.0, 5.0 mm or more larger than the maximum body conduit diameter. The personalized, bioresorbable, polymeric stent can have a diameter 0.01% to 5% larger than the maximum body conduit diameter.

[0006] An embodiment provides a method of implanting a personalized, bioresorbable, polymeric stent in a subject. The method can include: (a) preparing a body conduit in a subject for implantation by creating a first end and a second end of the body conduit; (b) inserting the stent into the first end of the body conduit and into the second end of the body conduit so that at least part of the first end of the body conduit covers at least a portion of a first end of the stent and at least a portion of the second end of the body conduit covers at least a portion of a second end of the stent; and (c) suturing the stent to the body conduit. The body conduit can be an esophagus, a trachea, an urethra, a large intestine, or a small intestine.

[0007] In an embodiment, a stent can be formed by: (a) imaging a body conduit of the subject to form an image of the body conduit; (b) determining a maximum body conduit diameter from the image; (c) using computer aided design to produce a body conduit design using the maximum body conduit diameter or a larger diameter; and (d) making the personalized, bioresorable polymeric stent based on the body conduit design using 3D printing. The first end of the body conduit can cover the first end of the stent and the second end of the body conduit can cover the second end of the stent, such that the first end of the body conduit can be in contact with the second end of the body conduit, such that the stent can be covered by both the first and second ends of the body conduit. The stent can be bioresorbed by the subject and does not need to be removed from the subject. The subject can be a mammal. A stent can have a diameter of about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.25, 1.5, 1.75, 2.0, 3.0, 4.0, 5.0 mm or more larger than the maximum body conduit diameter. The stent can have a diameter 0.01% to 5% larger than the maximum body conduit diameter. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Various objectives, features, and advantages of the disclosed subject matter can be more fully appreciated with reference to the following detailed description of the disclosed subject matter when considered in connection with the following drawings, in which like reference numerals identify like elements.

[0009] FIG. 1 panels A-D show in one embodiment, a concept and inspiration for personalized absorbable gastrointestinal stents. FIG. 1 panel A shows a flowchart where gastrointestinal tract occlusion or perforation is detected. CT imaging is used to determine the dimensions of the diseased part of the intestine. The dimensions of the diseased part of the intestine are utilized in computer-aided design (CAD) software to generate a personalized stent. The stent is fabricated using 3D-printing. The diseased part of the small intestine is removed, and the biodegradable stent is placed in the remaining healthy intestinal tissue. The stent is sutured in place such that the ends of the healthy tissue are allowed to rest outside the stent. The stent will then degrade with time, allowing healthy tissue segments to heal. FIG. 1 panels B-D shows a clinical case which occurred at Carle Foundation Hospital. A sleeve gastrectomy led to complications including sepsis.

[0010] FIG. 2 panels A-E show mechanical analysis of film and filament samples. (A) Representative stress-strain curves for films of each composition. Inset depicts linear region used for calculation of modulus of elasticity. (B) Film average modulus of elasticity for each composition. The 25:75 PCL: PDO ratio exhibits the highest modulus, with modulus generally increasing with increased PDO content. Double asterisks indicate statistical significance with a < 0.05. Single asterisks indicate statistical significance with a < 0.11. Error bars represent standard error. (C) Average yield strength for each composition. The 25:75 PCL: PDO ratio exhibits lower yield strength than the 75:25 PCL: PDO composition. Double asterisks indicate statistical significance with a < 0.01. n=3 for all samples except PDO, for which n=2 as one sample did not yield. (D) Representative stress-strain curves for filaments tested at room temperature and at physiological temperature. (E) Average modulus of elasticity for filaments tested at room temperature and at physiological temperature. Temperature change did not lead to a statistically significant change in modulus.

[0011] FIG. 3A-E show computer-aided design and finite element analysis (FEA) for three different designs, cylindrical, reinforced cylindrical, and curved. FIG. 3 panel A shows three proposed stent designs used in FEA analysis. The cylindrical design was a simple thin-walled cylinder with a constant inner and outer diameter. The reinforced cylindrical design incorporated rims at the two ends of the stent. These rims would double the thickness in the rimmed areas compared to the un-rimmed areas, while the inner diameter remained unchanged. The third design was a curved design, in which both the inner and outer diameters increased from their minimum values at the center of the stent to their maximum values at the two ends of the stent, with the thickness remaining constant throughout. A length of 60 mm and a minimum outer diameter of 30 mm were maintained for all designs. Four different stent thicknesses were evaluated for each design (1 mm, 0.75 mm, 0.5 mm, 0.25 mm). FIG. 3 panel B shows applied pressure and motion constraints on a model stent. The arrows indicate the uniformly distributed applied internal pressure. The markings indicate the suture holes which were constrained to remain in fixed positions. The tag indicates the assigned material properties based on the 25:75 PCL: PDO filament properties. FIG. 3 panel C shows locations of minimum and maximum deformation for each stent design. The cylindrical and curved designs exhibit maximum deformation at stent edges, while the reinforced cylindrical design displays a shift in maximum deformation closer to the center of the stent. Scale units are in mm. FIG. 3 panel D shows maximum deformation as a function of stent design and thickness. The reinforced cylindrical design experienced the least deformation. FIG. 3 panel E shows maximum stress as a function of stent design and thickness. The reinforced cylindrical design experienced the lowest maximum stress. [0012] FIG. 4A-C show composite characterization and stent degradation. (A) Scanning electron microscopy images of the 25:75 PCL: PDO film. Images show a uniformly mixed concave surface design and thickness. (B) FT-IR spectra for the polymers, composite, and filament. Characteristic C=0 peak (black arrow) from the ester bond is present in the polymers, composite, and filament. (C) Degradation behavior of 3D-printed stent segments in simulated intestinal fluid (SIF) and fetal bovine serum (FBS). An approximately 20% loss in mass is observed over a period of 20 days.

[0013] FIG. 5A-E show cell viability, proliferation, and adhesion. Panel A shows cell viability as determined from metabolic activity of human intestinal cells exposed to various concentrations of the polymer, composite, or filament. When exposed to a low mass (10 mg) of the materials, human intestinal cells did not show any significant change in metabolic activity. However, when exposed to a higher mass (100 mg) of the materials, the PCL, PDO, and composite all appeared to induce a reduction in cell metabolic activity, indicating possible cytotoxic effects. Despite this, the filament was still found to have cell metabolic activity that was comparable to the control, even at the higher dose. The filament shows high viability even for a high mass, while the PCL alone, PDO alone, and composite show a decrease in cell viability for higher doses of material. Error bars represent standard deviation. Single asterisks indicate statistical significance with a < 0.05. Double asterisks indicate statistical significance with a < 0.01. Panel B shows sample weight after exposure to cells and being washed. No statistically significant changes were observed. The materials themselves did not show a change in mass after exposure to the cells, indicating that cells were not seeded within the material surface. Values are expressed as percent of the initial weight for each sample. Error bars represent standard deviation. Panel C shows cell viability for cells grown on the materials. At the low concentration, PCL and PDO reduce cell viability, while the filament increases cell viability. At the high concentration, the filament increased cell viability. These results suggest that the filament can provide a surface on which cells can grow and proliferate, potentially aiding in healing the intestinal segments after stent placement. Error bars represent standard deviation. Single asterisks indicate statistical significance with a < 0.1 . Double asterisks indicate statistical significance with a < 0.05. Panel D shows sample weight after exposure to cells and being washed. No statistically significant changes were observed, indicating that the cellular material did not penetrate the samples, and was easily removed via washing of the samples. Values are expressed as percent of the initial weight for each sample. Error bars represent standard deviation. Panel E shows scanning electron microscopy images of stent segments on which cells were seeded. Cells were found to adhere to the stent surface, even just 14 h after cells were seeded on top of the stent surface. Adhesion of the cells to the 3D-printed stents indicates the potential for stents to serve as a surface upon which the intestine can be repaired.

[0014] FIG. 6 shows blood morphology after exposure to calcium chloride, polymers, composite, and filament. A blood spear preparation was performed to observe morphological changed in lymphocytes and blood clumping using clinical microscopy technique (conventional light microscopy) under high power field. No significant clumping or morphological changes in red blood cells were observed after being exposed to the PCL, PDO, composite, or filament. This indicates that these materials will not lead to adverse effects when interacting with blood at the surgical site. Images primarily depicted red blood cells rather than lymphocytes, as blood has a higher concentration of red blood cells than lymphocytes.

[0015] FIG. 7A-D. Stent placement in ex vivo pig intestines. (A) Incorporation of two intestinal segments over a model stent. The stent was 3D-printed with a commercially available material as proof of concept. (B-C) Demonstration of ability of stent-intestine combination to retain liquid without leakage. Arrows indicate suture locations and the position of non-sutured hole, and an arrow indicates the point of fluid injection into the intestinal lumen. (D) Screen captures show time-sequence for this ex vivo study over approximately 30 sec, starting with liquid administration (2 sec), application of pressure to mimic biological scenario (12 sec) and demonstrated stability of the stent and the sutured hole (20 sec).

[0016] FIG. 8 shows computerized tomography (CT) images of pigs used fo rin vivo study. Small intestine dimensions (16.78, 14.37 mm) and large intestine dimensions (29.32, 14.91 , 15.72 mm) are annotated. The animals were scanned on a General Electric Light speed 16-slice CT scanner (GE, Milwaukee, Wl, USA) using the following parameters: slice thickness: 0.625 mm; tube voltage: 80 kV; tube current: 100 mA; gantry rotation time: 0.8 s; and pitch: 9.38 mm.

[0017] FIG. 9 shows placement in in vivo intestines. An abdominal incision was made, and a segment of the small intestine was cut. The 3D-printed 25:75 PCL: PDO stent was then sutured in place.

[0018] FIG. 10A-D show stent placement in perforated in vivo pig intestines. Panel A shows 3D-printed curved stents of 4 different sizes. Panel B shows an abdominal incision being made. Panel C shows a gastrointestinal incision being made and a stent being placed. After stent placement, the intestinal incision was left partially open. Inset depicts intestine prior to incision. Panel D shows the stent being secured in place with sutures and the intestine then being placed back within the pig.

[0019] FIG. 11A-D show images of a study of 4 pigs conducted to test the efficacy of PDO/PCL stents to protect repairs made in the small bowel. Panel A shows five 3D- printed stents. Panel B shows 3D-printed stents implanted in a pig enterectomy model. Panel C shows one of the pigs. All animals were eating and healthy at the 16-day termination of the study. Panel D shows significant healing of the enterotomy in one of the pigs.

[0020] FIG. 12A-B show CT images taken one week post-surgery. Panel A shows co-localization of surgical clips (arrows) in the plane of the slice, which indicates no migration of the stent. Panel B shows the stent wall and surgical clips visible in stent cross sections.

[0021] FIG. 13A-C show three steps of stent implantation. Panel A shows an initial stent sizing, which is approximated by measuring the external circumference of the compressed bowel segment. Panel B shows an appropriately sized stent, labeled with a metal surgical clip, is inserted in the enterotomy in the bowel. Panel C shows that at both the proximal and distal ends, the stent is sutured to the bowel with 6-8 simple interrupted sutures through the small intestine wall using the pre-existing suture holes in the stent. A surgical clip is sutured to the exterior of the bowel during stent fixation to aid in identifying enterotomy site in CT scans. The enterotomy is sutured closed following stent placement. Preliminary studies left a 1.0 to 1.5 cm opening in the enterotomy to examine the stent’s ability to isolate the enterotomy site from the lumen of the bowel. [0022] FIG. 14 shows a Scanning Electron Microscopy (SEM) image of stent removed two weeks after implantation. Cracks show the beginnings of structural degradation. The box represents an approximate region of interest that is enlarged in the middle and right-side panes.

[0023] FIG. 15A-B show histology of intestinal enterotomy region approximately two weeks after stent implantation. Panel A shows 15 X magnification of the enterotomy region showing bridging of the enterotomy with connective tissue (arrows). Panel B shows the region in Panel A delineated by the red box viewed at 100X magnification showing intestinal epithelium forming on the surface of the tissue bridging the enterotomy.

[0024] Detailed Description

[0025] The use of 3D-printed bioresorbable polymeric stents can provide patients with a stent that can prevent leakage, is tailored specifically to their geometry, and can be usable within the small bowel, which is not amenable to endoscopic stent placement. [0026] Small intestine perforations, obstructions and enterocutaneous fistula are potentially life-threatening surgical conditions. They can be related to bowel obstructions, acute mesenteric ischemia, inflammatory bowel disease, foreign body ingestion or due to iatrogenic (laparoscopic access, takedown of adhesions, endoscopy) or non-iatrogenic traumatic mechanisms. Perforations of the bowel can lead to infection and degradation of the tissue such that it is impossible to repair without risking a leak. Obstructions can similarly cause injury to the wall of the bowel. If the bowel is repaired or re-connected after a portion of bowel has be removed, there is a risk for leak at the site of the connection. Underlying injury or inflammation of the bowel from infection, edema, dilation or injury increase the risk of a leak. Anastomotic leaks can be quite morbid and have significant consequence to the patient. One commonly used surgical maneuver is the resection of a segment of small bowel. This may be done for ischemia, perforation, inflammatory bowel disease, or any other reason that causes the small bowel to be nonviable. This involves removal of the diseased portion of the small bowel, after which the two ends of the remaining healthy tissues are anastomosed, or re-connected, with either staples or sutures. Patients undergoing such procedures face the risk of anastomotic leakage and/or infection. In a study of 1223 patients who had undergone intestinal anastomosis, Hyman et a\. (Anastomotic Leaks After Intestinal Anastomosis. Ann. Surg. 2007, 245 (2), 254-258) found that 2.7% of these patients experienced anastomotic leakage. The alternative is creation of a stoma which is a purposeful connection of the bowel to the skin such that all the intestinal contents come through the skin into a bag, rather than as normal bowel movements.

[0027] One of the worst complications from an anastomotic leak or small intestinal perforation is an enterocutaneous fistula (EOF), or a connection from the bowel to the skin which lets some of the intestinal contents to continuously leak through the fistula. These are complicated problems to fix, and generally require at least one more major surgery to reverse. An estimated 90% of patients will experience an ECF-related morbidity ranging from skin excoriation, to dehydration, to sepsis. The mortality attributable to an ECF ranges anywhere from 5-20% and is dependent on number of factors including underlying infection and fistula location. Because the leading cause of death in patients with ECF is sepsis, control of the contamination from a leak or perforation remains one of the cornerstones of therapy. Current management for ECF generally consists of initial nonoperative management followed by delayed surgical repair in order to manage inflammatory, infectious, nutritional, and wound complications. This process can involve extended patient hospitalizations and frequent readmissions, prolonged parenteral nutrition dependency, profound electrolyte deficiencies, and extensive wound management requirements. While approximately 25% of ECF fistulae will heal with nonoperative treatment, the majority will require definitive surgical repair which is generally delayed for at least 6-12 months to allow for intrabdominal inflammation and adhesions to resolve, resulting in very significant patient morbidity and mortality as well as sizable healthcare costs.

[0028] Current clinical practices allow for the utilization of endoscopically placed, self-expandable, covered metallic gastrointestinal stents in the setting of esophageal or colonic perforations or fistulae. These commercially available stents allow diversion of luminal contents through the stent to bypass the healing anastomosis or area with leak and effectively reduce inflammation, infectious complications, and fluid losses while simultaneously allowing for continued oral nutrition. In most cases, this allows the Gl tract to heal without further surgical intervention. The non-absorbable stents are then removed endoscopically after approximately 4-6 weeks. Unfortunately, placement of synthetic, non-absorbable stents in the esophagus and colon via endoscopic approaches is limited to these anatomic locations as the small bowel is not amenable to endoscopic stent placement given the distance from the mouth or anus. Furthermore, commercially produced stents are currently manufactured in a narrow range of sizes, further limiting their applicability in other portions of the Gl tract. Lastly, endoscopic procedures themselves can sometimes cause some complications, including causing perforations, leakage, and fistulas.

[0029] Provided herein are biodegradable stents that can be placed during, for example, small bowel resection or during the repair of a perforation. These stents do not require endoscopic placement or removal, degrade with time, and prevent leakage from the interface between the two segments of healthy tissue, for example intestinal tissue in an anastomosis or at the site of a repair. These stents can advantageously also be used in other body conduits.

[0030] Polymers

[0031] Personalized, bioresorbable, polymeric stents as described herein can be made up of one or more suitable polymers. A “polymer” includes a product of a polymerization reaction inclusive of homopolymers, copolymers, terpolymers, etc., whether natural or synthetic, including random, alternating, block, graft, branched, cross-linked, blends, compositions of blends and variations thereof. A polymer can be bioresorbable, biocompatible or biodegradable. Examples of polymers include one or more of glycolic acid; lactic acid; 1 ,4-dioxanone, trimethylene carbonate; poly- or 3- hydroxybutyric acid; e-caprolactone; polyglycolic acid; poly(lactideco-glycolide); poly(glycolic acid-co-trimethylene carbonate); polylactic acid; poly-D,L-lactic acid; poly-L-lactic acid; polydioxanone; polycaprolactone; poly(lactide-co-caprolactone); poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoates; polyester; polycarbonate; phosphorylcholine; tyrosine polycarbonate; polyamide; polypeptide; poly(amino acids); polyester; polyesteramide; poly(alkylene alkylate); polyether; polyethylene glycol; polyethylene; polyethylene terapthalate; ethylene vinyl acetate; ethylene vinyl alcohol; polyvinyl pyrrolidone; polyurethane; polyetherester; polyacetal; polycyanoacrylate; poly(oxyethylene)/polyoxypropylene) copolymer; polyacetal; polyketal; polyphosphate; polyacrylamide; polyphosphoester; polyphosphoester urethane; polysiloxane; poly(iminocarbonate); aliphatic polycarbonates; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid); silk; chitin; chitosan; polysaccharide; poly(hydroxybutyrate-co-valerate); fibrin; fibrinogen; cellulose; starch; collagen; poly-4-hydroxybutyrate; and combinations thereof.

[0032] A polymer or stent can be supplemented, coated, further treated, or chemically modified with one or more bioactive agents or bioactive compounds. A bioactive agent or bioactive compound is a compound or entity that can alter, inhibit, activate, or otherwise affect biological or chemical events. For example, bioactive agents or compounds can include, but are not limited to, collagen, insoluble collagen derivatives, antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, Chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamycin, etc.; immunosuppressants; anti-viral substances such as substances effective against hepatitis; enzyme inhibitors; hormones; neurotoxins; opioids; hypnotics; anti-histamines; lubricants; tranquilizers; anti-convulsants; muscle relaxants and anti-Parkinson substances; anti-spasmodics and muscle contractants including channel blockers; miotics and anti-cholinergics; anti-parasite and/or anti protozoal compounds; modulators of cell-extracellular matrix interactions including cell growth inhibitors and antiadhesion molecules, vasodilating agents; inhibitors of DNA, RNA, or protein synthesis; anti-hypertensives; analgesics; anti-pyretics; steroidal and non-steroidal anti-inflammatory agents; anti-angiogenic factors; angiogenic factors and polymeric carriers containing such factors; anti-secretory factors; anticoagulants and/or antithrombotic agents; local anesthetics; prostaglandins; anti-emetics; imaging agents; biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids; peptides; vitamins; inorganic elements; co-factors for protein synthesis; endocrine tissue or tissue fragments; synthesizers; enzymes such as alkaline phosphatase, collagenase, peptidases, oxidases and the like; polymer cell scaffolds with parenchymal cells; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells; natural extracts; genetically engineered living cells or otherwise modified living cells; expanded or cultured cells; DNA delivered by plasmid, viral vectors, or other member; tissue transplants; autogenous tissues such as blood, serum, soft tissue, bone marrow, or the like; bioadhesives; fibronectin (FN); endothelial cell growth factor (ECGF); vascular endothelial growth factor (VEGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (EGF); interleukins, for example, interleukin-1 (IL-1), interleukin-2 (IL-2); human alpha thrombin; transforming growth factor (TGF-beta); insulin-like growth factors (IGF-1 IGF-2); parathyroid hormone (PTH), platelet derived growth factors (PDGF); fibroblast growth factors (FGF, BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamel matrix proteins; growth and differentiation factors (GDF); protein receptor molecules; small peptides derived from growth factors above; cytokines; somatotropin; antitumor agents; cellular attractants and attachment agents; immunosuppressants; permeation enhancers, for example, fatty acid esters such as laureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto aldehydes; and nucleic acids.

[0033] In certain embodiments, a bioactive agent or compound can be a drug, a growth factor, a protein, ora combination thereof. In some embodiments, the bioactive agent can be a growth factor, cytokine, extracellular matrix molecule, or a fragment or derivative thereof, for example, a protein or peptide sequence such as arginylglycylaspartic acid (“RGD”).

[0034] Polycaprolactone (PCL) exhibits excellent mechanical and degradability properties. It also has good flexibility and elasticity, which is much needed during peristaltic movement. Polydioxanone (PDO) is a bioreabsorbable polymer which degrades by hydrolytic processes resulting in low molecular weight species that can be metabolized or absorbed by the body. The end products are excreted in urine or eliminated by digestion or exhaled as CO2. PCL and PDO both are FDA-approved polymers, and have excellent biocompatibility and biodegradability. Both polymers contain a hydrolysable ester bond, which gives them their biodegradability.

[0035] In an embodiment, a personalized, bioresorbable, polymeric stent can be made up of a polymer comprising polydioxanone and polycaprolactone. Polydioxanone and polycaprolactone can be present in a stent in a ratio of about 10:90, 20:80, about 25:75; about 30:70, about 40:60, about 50:50; about 60:40, about 75:25, or about 80:20.

[0036] A polymer composite can be formed into a filament, which can be used in a commercially available 3D-printer to print a stent with the desired dimensions.

[0037] Stent

[0038] A body conduit stent can be in the shape of a cylinder with a central bore. A cylinder can have straight parallel sides and a circular or oval cross section. In an embodiment a cylinder does not have straight parallel sides, but has a curved or S- shaped tubular shape. In one embodiment, a cylinder can comprise, for example, a simple thin-walled cylinder with a constant inner and outer diameter. In another embodiment, a cylinder can comprise thicker rims at the two ends of the stent. The rims can have a greater thickness than the rest of the stent. For example about 1.1 , 1.2, 1.5, 1.7, 2.0, 2.2, 2.5 times or more the thickness in the rimmed areas compared to the un-rimmed areas). A rim can extend from an end of a stent towards the other end of the stent for about 0.01 , 0.1 , 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10 mm or more (that is, the rim is about 0.01 to about 10 mm in length). An inner diameter of the stent can remain unchanged, can increase as it approaches the ends, or decrease as it approaches the ends.

[0039] In a further embodiment, a cylinder can be “curved” as in that both the inner and outer diameters can increase from their minimum values at the center of the stent to their maximum values at each of the two ends of the stent, with the thickness of the stent remaining constant throughout. The maximum values of the inner and outer diameters can differ from the minimum values by about 0.1, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 30, 40% or more. For example, if an inner diameter minimum value at the center of the stent is 5.0 mm and the inner maximum value at the end of the stent is 6.0 mm, then the values differ by about 16.7%. In an embodiment, the maximum values of the inner and outer diameters can differ from the minimum values of the inner and outer diameters by about 0.01 , 0.1 , 0.25, 0.5, 0.75, 1.0, 1 .5, 2.0, 3.0, 4.0, 5.0 mm or more (or any range between about 0.01 and 5.0 mm).

[0040] A “central bore” is the hollow space that the cylindrical stent envelops. The diameter of the central bore can vary inversely to the thickness of the stent. A stent can have a thickness of about 0.01 , 0.1 , 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 3.0 mm or more (or any range between about 0.01 and 3.0 mm). A stent can be about 0.1 , 0.5, 1.0, 2.5, 5, 0, 7.5, 10, 15, 20, 25, 30, 40, 45, 50, 60, 70, 80, 100 mm or more in length (or any range between about 0.1 and 100 mm).

[0041] In an embodiment, the stent is not permeable to fluids, particles, or gases that are directed through the stent (e.g., small or large intestinal fluid/contents, food, atmospheric oxygen, or urine).

[0042] The inner diameter of the stent can be about 0.01, 0.1 , 0.5, 1.0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 cm or more (or any range between about 0.01 and 10.0 cm, for example about 1.75 cm to about 3.5 cm).

[0043] The outer diameter of the stent can be about 0.01 , 0.5, 1.0, 1 .5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 cm or more (or any range between about 0.01 and 10.0 cm, for example about 1.75 cm to about 3.5 cm).

[0044] A stent can comprise about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more suture holes at each end of the stent. In an embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more suture holes can be present at any point along the stent. [0045] A stent can have an outer diameter and inner diameter. The outer diameter of the stent can be larger at the ends of the cylinder as compared to the outer diameter at the middle of the stent. For example, the outer diameter of the stent at the ends of the stent can be about 0.1 , 0.5, 0.75, 1.0, 1 .25 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.75, 4.0, 5.0 or more mm larger (or any range between about 0.1 and 5.0 mm larger) than the outer diameter of the stent at the middle of the stent.

[0046] The thicknesses of the ends of the stent can be greater than that of the thickness of the remainder (e.g., the portion of the stent that is not part of the thickened rims) of the cylinder forming thickened rims at each end of the cylinder. The rims of the cylinder can be about 0.1 , 0.25, 0.5, 0.75, 1.0, 2.0, 3.0, 4.0, 5.0 mm or more thicker (or any range between about 0.1 and 5.0 mm) than the remainder of the cylinder. [0047] In some embodiments, a stent polymer may have a modulus of elasticity of about 100, 125, 150, 175, 200, 211 , 225, 250, 275, 300 or more MPa.

[0048] Biodegradable or bioreabsorbable means that the stent will degrade over time by the action of enzymes, by hydrolytic action, and/or by other similar mechanisms in the subject’s body. In various embodiments, a biodegradable or bioreabsorbable stent can break down or degrade within the body to non-toxic components as cells or fluids infiltrate the stent and allow repair of any defect. Stents described herein can erode or degrade over time due, at least in part, to contact with substances found in the surrounding tissue, fluids or by cellular action. Bioresorbable stents can be broken down and absorbed within the human body, for example, by a cell or tissue. Stents as described herein can be biocompatible, meaning that the stents will not cause substantial tissue irritation or necrosis at the target tissue site and/or will not be carcinogenic.

[0049] Methods of Making Personalized, Bioresorbable, Polymeric Stents

[0050] Methods of making personalized, bioresorbable, polymeric stents are provided. A stent that is “personalized” is one that is made for a specific patient such that the stent substantially duplicates or mimics the dimensions a patient’s body conduit. Stents can be personalized by imaging a patient’s body conduit, which can then be converted to a digital data set, a digital body conduit model, and/or fabrication instructions.

[0051] A body conduit stent can be imaged to provide a digital data set that can be converted to a digital body conduit stent design and/or fabrication instructions. Imaging can be done by obtaining one or images of a body conduit of a patient by, for example, computerized tomography (CT) (e.g., Philips Precedence™ (Brilliance) 16 channel CT imaging device), magnetic resonance imaging (MRI), x-ray, a cone beam imaging device, or ultrasound. The one or more images can provide one or more dimensions of a body conduit. The dimensions can be, for example, length, inner diameter, outer diameter, maximum inner diameter (the greatest diameter of the conduit measured over a particular length), maximum outer diameter (the greatest diameter of the conduit measured over a particular length) and/or thickness of the body conduit. A particular length can be about 10, 20, 30, 40, 50, 100, 500 mm or more. A stent can be designed using the maximum diameter (i.e. , an average of the maximum inner diameter and the maximum outer diameter), the maximum inner diameter, or the maximum outer diameter. In an embodiment a stent is designed have a diameter slightly larger than the maximum diameter (i.e., an average of the maximum inner diameter and the maximum outer diameter), maximum inner diameter, or maximum outer diameter. In an embodiment a stent inner or outer diameter is about 0.01 , 0.1 , 0.5, 1.0, 1.25, 1.5, 1.75, 2.0, 3.0, 4.0, 5.0 mm or more larger (or any range between about 0.01 mm and 5 mm, for example between about 0.01 mm and 4mm or between about 0.01 and 2mm) than the measured maximum diameter (i.e., an average of the maximum inner diameter and the maximum outer diameter), maximum inner diameter, or maximum outer diameter of a patient’s body conduit. In an embodiment a stent inner diameter or outer diameter is about 0.01 , 0.1 , 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15% or more larger (or any range between about 0.01 and 15%, for example between about 0.01 and 10% or between about 0.01 and 10%) than the measured maximum diameter (i.e., an average of the maximum inner diameter and the maximum outer diameter), maximum inner diameter, or maximum outer diameter of a patient’s body conduit.

[0052] Computer aided design (“CAD”) and computer aided manufacturing (CAM) techniques can be used to produce a digital body conduit stent design and/or fabrication instruction from the imaging data set.

[0053] The one or more images of a body conduit having a shape and a size, can be used to create a digital data set characterizing a shape and a size of the body conduit. The digital data set can be converted into a digital body conduit stent design and/or fabrication instructions. The fabrication instructions can be used to form a body conduit stent with a shape and a size substantially matching the shape and size of the subject’s body conduit. In certain embodiments, depending on needs, fabrication instructions can be used to form a body conduit stent with a shape and a size slightly different from the shape and size of the subject’s body conduit. For example, a stent can be designed with a slightly larger or smaller inner or outer diameter. The length of the stent can be selected to be useful in correcting a defect or disease in a subject’s body conduit.

[0054] Transforming the digital data set to a digital body conduit stent design or fabrication instructions can comprise transferring the digital data set into a computer aided design or computer aided manufacturing (CAD/CAM) system. CAD software can be, for example, Creo Parametric 3D modeling Software (PTC Inc., Boston MA), BlocksCAD (Boston, MA), Fusion 360° (AutoDesk, San Rafael CA), or Rhino (Robert MeNea! and Assc., (Seattle WA).

[0055] A digital body conduit stent design or fabrication instructions can be stored in a database coupled to a processor, the processor having instructions for retrieving the stored digital body conduit stent design or fabrication instructions.

[0056] A body conduit stent can be produced by instructing, for example, a 3D printer to print a stent using suitable polymer based on the stored digital body conduit stent design and/or fabrication instructions.

[0057] A personalized, bioresorbable, polymeric stent can be made using the digital body conduit stent design and/or fabrication instructions and additive manufacturing. An additive manufacturing process can be micro-stereolithography (e.g., 3D printing). “Three-dimensional printing system," "three-dimensional printer," and "printing," describe various solid freeform fabrication techniques for making three-dimensional articles or objects by selective deposition, jetting, fused deposition modeling, multijet modeling, and other additive manufacturing techniques that use a build material or ink to fabricate three-dimensional objects.

[0058] Examples of 3D printing systems include MakiBox A6 (Makible Limited, Hong Kong); CubeX (3D Systems, Inc., Circle Rock Hill, S.C.); 3D-Bioplotter (EnvisionTEC GmbH, Gladbeck, Germany); Airwolf 3D HD printer (Fountainview CA); Dremel (DigiLab Mount Prospect IL); and Ultimaker 3D (Ultrecht Netherlands).

[0059] A 3D printing device can include a controller or processor to accept instructions and automatically manufacture a body conduit stent, based on the digital body conduit stent design and/or fabrication instructions. In one example, a processor can comprise memory for temporary or permanent storage of fabrication instructions. Various instructions can be programmed and stored in memory to make multiple designs of a body conduit stent. In some embodiments, a 3D printing device can include an input device, such as, for example, a keyboard to input commands and instructions. In some embodiments, a processor of a 3D printing device can be configured to receive commands and instructions from an external computer. For example, fabrication instructions can be stored and executed locally on an external computer or processor to operate a 3D printing device. A computer and 3D printing device can be one single device with component parts.

[0060] In an embodiment, a processor comprises logic to execute one or more instructions to carry out instructions of the computer system (for example, transmit instructions to the 3D printer). The logic for executing instructions can be encoded in one or more tangible media for execution by processor. For example, a processor can execute codes stored in a computer-readable medium such as memory. The computer-readable medium may be stored in, for example, electronic (for example, RAM (random access memory), ROM (read-only memory), EPROM (erasable programmable read-only memory), magnetic, optical (for example, CD (compact disc), DVD (digital video disc)), electromagnetic, semiconductor technology, or any other suitable medium.

[0061] In an embodiment a computer implemented method for producing a body conduit stent is provided. The computer implemented method for producing a body conduit stent can include obtaining a 3D image of a body conduit of a subject, generating a 3D digital model of the body conduit based on the 3D image of the body conduit site of interest, the 3D digital model of the body conduit being configured to fit in the intended graft site. The 3D digital model can be stored on a database coupled to a processor, the processor having instructions for retrieving the stored 3D digital model of the body conduit. The processor also has fabrication instructions for instructing a 3D printer to produce a body conduit stent.

[0062] A computer implemented method can produce a body conduit stent by instructing the 3D printer to print the body conduit stent using a suitable polymer based on the stored 3D digital body conduit stent design or fabrication instructions.

[0063] 3D printing systems can include, for example, an illuminator, a dynamic pattern generator, an image-former, and a Z-stage. The illuminator can include, for example, a light source, a filter, an electric shutter, a collimating lens, and a reflecting mirror that projects a uniformly intense light on a digital mirror device (DMD), which generates a dynamic mask. It is noted, however, the methods described herein are not limited to any particular additive manufacturing system or process.

[0064] An additive manufacturing system can be configured to fabricate a body conduit stent using dynamic mask projection micro-stereolithography. This process can include producing 3D microstructural scaffolds by slicing a 3D model with a computer program and solidifying and stacking images layer by layer in the system. A reflecting mirror of the system can be used to project a uniformly intense light on the digital mirror device, which generates a dynamic mask. The dynamic pattern generator creates an image of the sliced section of the fabrication model by producing a black- and-white region similar to the mask. To stack the images, a resolution Z-stage moves up and down to refresh the polymer surface for the next curing. A Z-stage build subsystem, can include a platform for attaching a substrate, a vat for containing the polymer liquid solution, and a hot plate for controlling the temperature of the solution. The Z-stage makes a new solution surface with the desired layer thickness by moving downward deeply, moving upward to the predetermined position, and then waiting for a certain time for the solution to be evenly distributed.

[0065] Body conduit stents or stent elements can be manufactured as a sheet via an additive manufacturing process or other suitable process and wrapped into cylindrical form. Alternatively, stents or stent elements can be manufactured in cylindrical form using an additive manufacturing process.

[0066] Methods of Implanting a Personalized, Bioresorbable, Polymeric Stent [0067] A body conduit stent can be used to correct a diseased or defective body conduit in a subjection. In an embodiment, the diseased or defective portion of the body conduit is surgically removed and two healthy ends of the conduit are produced. The personalized, bioresorbable, polymetric stent, replicating the diameter of the diseased or defective area or having a slightly larger or smaller diameter than the subject’s body conduit maximum diameter can be sutured in place and the ends of the healthy tissue are allowed to rest outside the stent. In an embodiment, a subject’s body conduit maximum diameter can be obtained by capturing both the maximum outer body conduit diameter and the maximum inner body conduit diameter and obtaining an average measurement. The stent prevents the occurrence of leakage at the interface between the two intestinal segments and will degrade over time to eliminate the need for removal post-healing. [0068] A personalized, bioresorbable, polymeric stent as described herein is inserted into the first end of the body conduit and into the second end of the body conduit so that at least part of the first end of the body conduit covers at least a portion of a first end of the stent and at least a portion of the second end of the body conduit covers at least a portion of a second end of the stent. The stent can be sutured to the first end and to the second end of the body conduit such that the ends of the healthy tissues rest outside the stent. Over time the stent structure is bioabsorbed such that no portion of the stent remains within the body. Having degraded over time, the bioresorbable stent eliminates the need for removal post healing. What remains is a healed, continuous body conduit.

[0069] In an embodiment the first end of the body conduit covers the first end of the stent and the second end of the body conduit covers the second end of the stent, such that the first end of the body conduit is in contact with the second end of the body conduit, and such that the stent is covered by both the first and second ends of the body conduit. The healthy tissue ends of the body conduit can touch each other over the stent, come within 0.01, 0.5, 1.0, 2.0 mm or more of each other, or overlap over the stent by about 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10 mm or more. In an embodiment, the healthy tissue ends of the body conduit can be sutured to each other, sutured to the stent, or both. In an embodiment, the heathy tissue is sutured to the stent at each end of the stent.

[0070] A body conduit can be, for example, an esophagus, a trachea, an urethra, a large intestine, or a small intestine.

[0071 ] A stent can be bioresorbed by the subject and does not need to be removed from the subject. In an embodiment, when a segment of a body conduit such as an intestine is resected with a bioresorbable stent, the two ends of the remaining healthy tissue can be connected. Over time the stent structure is bioabsorbed such that no portion of the stent remains within the body. Having degraded over time, the bioresorbable stent eliminates the need for removal post healing. What remains is a healed, continuous intestine. In an embodiment, a body conduit stent loses 10, 20, 30, 40, 50, 60, 70, 80, 90% or more mass over 1 week, 1 , 2, 3, 4, 5, or more months. In an embodiment, a body conduit stent loses 10, 20, 30, 40, 50% or more mass over 1 , 2, 3, 4, or more months.

[0072] A “patient” or “subject” as used herein can be a mammal, e.g., a human or a veterinary patient or subject, e.g., mouse, rat, rabbit, guinea pig, dog, cat, fox, horse, cow, pig, goat, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.

[0073] The compositions and methods are more particularly described below and the Examples set forth herein are intended as illustrative only, as numerous modifications and variations therein will be apparent to those skilled in the art. The terms used in the specification generally have their ordinary meanings in the art, within the context of the compositions and methods described herein, and in the specific context where each term is used. Some terms have been more specifically defined herein to provide additional guidance to the practitioner regarding the description of the compositions and methods.

[0074] As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. As used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference as well as the singular reference unless the context clearly dictates otherwise. The term “about” in association with a numerical value means that the value varies up or down by 5%. For example, for a value of about 100, means 95 to 105 (or any value between 95 and 105).

[0075] All patents, patent applications, and other scientific or technical writings referred to anywhere herein are incorporated by reference herein in their entirety. The embodiments illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations that are specifically or not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms, while retaining their ordinary meanings. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims. Thus, it should be understood that although the present methods and compositions have been specifically disclosed by embodiments and optional features, modifications and variations of the concepts herein disclosed can be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of the compositions and methods as defined by the description and the appended claims. [0076] Any single term, single element, single phrase, group of terms, group of phrases, or group of elements described herein can each be specifically excluded from the claims.

[0077] Whenever a range is given in the specification, for example, a temperature range, a time range, a composition, or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the aspects herein. It will be understood that any elements or steps that are included in the description herein can be excluded from the claimed compositions or methods.

[0078] In addition, where features or aspects of the compositions and methods are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the compositions and methods are also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

[0079] The following are provided for exemplification purposes only and are not intended to limit the scope of the embodiments described in broad terms above.

[0080] Examples

[0081 ] These examples focused on the rapid manufacturing of gastrointestinal stents composed of a polycaprolactone-polydioxanone (PCL-PDO) composite, but as described above, any suitable polymer or body conduit can be used. Dynamic Mechanical Analysis (DMA) tests were conducted to separately analyze the effects of composition, the filament formation process, and physiological temperature on the PCL- PDO material properties. The stent design was then modeled using computer-aided design, and Finite Element Analysis (FEA) was used to simulate the effects of physiologically relevant forces on stent integrity. The presence of hydrolysable ester bonds was confirmed using FT-IR spectroscopy. In vitro studies were used to evaluate the biocompatibility of the polymer composite. Further analyses were conducted through stent placement in ex vivo pig intestines. PCL-PDO stents were then 3D-printed and placed in vivo in a pig model.

[0082] Materials

[0083] Poly(caprolactone) (50,000 MW) was purchased from Polysciences, Inc. Poly(dioxanone) was purchased from Evonik Inc. 1 ,1 ,1 , 3, 3, 3, Hexafluoro-2-propanol (HFP) and 2,2’ Trifluoroethanol (TFE) were purchased from Sigma Aldrich and Alfa Aesar respectively. Calcium chloride was obtained from Sigma-Aldrich. Fresh whole pig blood was collected from the UIUC Meat Science Lab in citrate anticoagulant- treated tubes. Simulated Intestinal Fluid (SIF) USP test solution was purchased from VWR.

[0084] Polymer Composite Formation

[0085] Polymer composites were formed by dissolving varying mass ratios of PCL and PDO in HFP orTFE. Each polymerwas separately dissolved into the solvent (HFP or TFE) at a concentration of 8 mg/mL, and the solutions were then mixed and allowed to stir on a stir plate. Five different compositions were synthesized (Table 1). The composites were dried on a rotary evaporator under vacuum at a temperature of 50- 90 °C. In order to dry large quantities of the composite at a time, a custom-made flask was obtained from the UIUC glass shop. This allowed for the drying of 200-250 mL of the composite solution over a period of approximately 1-2 hours. Samples were left in a vacuum oven overnight to eliminate any remaining solvent.

[0086] Table 1. Various PCL: PDO compositions synthesized

[0087] Filament Formation

[0088] The dried polymer composite was cut into small pellets of about 3 mm by 3 mm to be used in filament formation. Preliminary experiments were conducted using a Filastruder. The filaments were formed at temperatures ranging from 90 to 100 °C, with an extrusion diameter of 2 mm. A Filabot was used for all further experiments. For Filabot extrusion, greatest extrusion success was found when the temperature was initially set to approximately 125 °C, after which it was lowered in intervals of 5- 10 degrees to 90 °C and the extrusion process was completed. An extrusion diameter of 2.85 mm was used.

[0089] Film Formation

[0090] Films for mechanical testing were formed by pouring 2 ml_ of the undried polymer composite into glass bottles with a diameter of approximately 2.5 cm. The composites were then allowed to dry in a vacuum desiccator.

[0091] Dynamic Mechanical Analysis (DMA)

[0092] Dynamic Mechanical Analysis testing was conducted in tension on a Q800 DMA at a force ramp of 1 N/minute with a maximum force of 18 N and a preload force of 0.001 N. Dynamic mechanical analysis was conducted on PCL, PCL:PDO 75:25, PCLPDO 50:50, PCLPDO 25:75, and PDO rectangular film samples cut from the dried composite films. Sample thickness, length, and width were recorded prior to testing. PCL: PDO 25:75 filament extruded with the Filastruder were tested at both room temperature and a temperature of 37°C. Filament length and diameter were recorded prior to testing. All tests were conducted in triplicate. The slope of the linear portion of the stress-strain curves was used to calculate the modulus of elasticity (E). The yield stress was calculated by drawing a line of slope E with an initial 0.2% strain offset and locating its point of intersection with the stress-strain curve.

[0093] Computer Aided Design (CAD) & Finite Element Analysis (FEA)

[0094] CAD and FEA were conducted in Creo Parametric. The stents were modeled as thin walled cylinders of various designs, with minimum outer diameters of 30 mm and varying thicknesses and geometries. The designs also incorporated 4 equally-spaced 1 mm diameter holes on each end to allow for suture placement. For FEA, a modulus of elasticity of 211 MPa was incorporated into the model based on the results of DMA experiments. The 4 holes on each end of the stent were constrained as having fixed positions, and an internal pressure of 1765 Pa was applied to each stent. This pressure was determined by taking the internal intestinal pressure and doubling it to incorporate a safety factor of 2. These parameters are summarized in Table 2.

[0095] Table 2. Parameters used for FEA study

[0096] Scanning Electron Microscopy (SEM)

[0097] SEM images of the PCL: PDO 25:75 film samples were taken. Samples were coated with gold-palladium before imaging with a JEOL 6060 Scanning Electron Microscope with an acceleration voltage of 5 kV.

[0098] 3D printing

[0099] Preliminary 3D printing was conducted using an Airwolf 3D HD printer at temperatures ranging from 180 °C to 220 °C. For in vivo studies, Dremel and Ultimaker 3D printers were used with extrusion temperatures of 180 °C and 210°C respectively. An Ultimaker 3D printer was used for ex vivo stent placement experiments.

[0100] FT-IR

[0101] FT-IR measurements were taken for PCL, PDO, the 25:75 PCL: PDO composite, and the 25:75 PCL: PDO filament. Measurements were taken using ATR- FTIR on a Thermo Nicolet Nexus 670 FT-IR. Samples were compressed into compacted disks prior to FT-IR measurement.

[0102] Degradation

[0103] Degradation studies were conducted on approximately 1 cm by 1 cm segments cut from 3D-printed stents. The dry weight of the stents was collected prior to degradation experiments. Samples (n=3 each) were placed in 20-mL glass scintillation vials and 15 mL of fetal bovine serum (FBS) or simulated intestinal fluid (SIF) were added to each vial. Vials were capped and incubated at 37 °C. Samples were dried and weighed at days 3, 6, 10, 15, and 20. Sample mass as a percentage of initial mass was calculated as follows:

Final Segment Mass

Percent Initial Mass = - _* 100 Percent

Initial Stent Segment Mass

[0104] FT-IR spectra were collected for SIF and heat-inactivated FBS, in addition to FBS and SIF samples that were incubated with stent samples. Samples were prepared by depositing 1 ml_ of liquid solution on MirrIR corner-frosted FT-IR slides and drying overnight in a vacuum oven. FT-IR spectra were collected using a Thermo Nicolet Nexus 670 FT-IR.

[0105] Cell Viability, Proliferation, and Adhesion [0106] Cell viability was assessed for ATCC CRL-7820 human intestinal cells grown in an A59224-well plate (60,000 cells per well). Plated cells were exposed to the material of interest (PCL, PDO, 25:75 PCL: PDO composite, or 25:75 PCL: PDO filament) for 48 hours. Each test was conducted in triplicate, and for varying masses of the material (10 mg and 100 mg). An MTT assay was used to measure cell metabolic activity after 48 hours, and cells were imaged with a Leica DM I 3000 B optical microscope for observation of morphological changes. The % cell viability was calculated as follows:

A592 sample treated cells -A592

% cell viability = * 100%

A592 untreated cells -A592 blank

[0107] After incubation with cells, samples were allowed to soak in deionized water for 1 hour, followed by drying in a vacuum oven. Samples were then weighed to calculate the mass as a percentage of the initial mass. A change in sample weight would provide insight into cell-sample interactions. The final sample mass % was calculated as follows:

A592 sample treated cells - A592 blank

% cell viability = - ^* 100%

A592 untreated cells - A592 blank

[0108] The ability of the materials to alter the cell attachment and survival properties was assessed by the simultaneous addition of cells and the material of interest to wells in an A592 24-well plate, followed by incubation for 3 days. As before, the tests were conducted in triplicate for varying masses of the materials (10 mg and 100 mg), viability was measured using an MTT assay, and samples were weighed after incubation and washing.

[0109] To determine the ability of the 3D-printed stents to provide a surface for cell attachment, segments of approximately 1.5 cm by 0.75 cm were cut from 3D-printed stents. Stent segments were pre-incubated in completed Dulbecco’s Modified Eagle Medium (DMEM) for two days, after which samples were individually placed in wells of a 12-well tissue-culture-treated plate. 1 mL of cell suspension containing CRL-7820 cells at a concentration of 114,000 cells/mL was added into each well, directly on top of the stent segment. Samples were incubated at 37°C for 14 h, after which the culture medium was removed. 2 mL of 4% paraformaldehyde solution was added to each well and the plate was incubated at room temperature for approximately 1 .25 h. Following this, the paraformaldehyde solution was removed and samples were dried by room temperature incubation for 10 min each with serially increasing concentrations of ethanol (25 %, 50 %, 75 %, 95 %, and 100 %). After incubation with 100 % ethanol, each sample was moved to a fresh well and allowed to dry in open air. Samples were not coated prior to SEM imaging, and images were acquired under low vacuum using a FEI Quanta FEG 450 ESEM.

[0110] Blood Smear

[0111] Blood smear experiments were conducted by exposing 150 pl_ of whole fresh pig blood to 25 mg of PCL, PDO, PCL: PDO 25:75 composite, PCL: PDO 25:75 filament, or to 0.025 M calcium chloride solution. Experiments were conducted in triplicate. The blood was smeared onto glass slides after 15 minutes of exposure to the material of interest, and optical microscopy images were taken with a Leica DM I 3000 B.

[0112] Feasibility of Placement In ex vivo Intestines with Surgical Incision [0113] Multiple stent designs were evaluated through ex vivo placement of stents in pig small intestines. The goal of these experiments was to determine the effect of stent design on ease of stent placement and in obtaining a secure fit. The ex vivo intestines were cut and measured, and stents were 3D-printed using a poly(lactic acid) (PLA) filament. This material was chosen for these ex vivo experiments due to its low cost and ease of access for proof of concept experiments with multiple stent designs. The stents were then sutured in place in the ex vivo intestines, and observations on the ease of placement and the security of the fit were recorded. The curved design was then selected for further evaluation. This design was sutured into place, and the original hole cut into the intestine was allowed to remain without further suturing. Additional tests were then conducted to evaluate hydrodynamic performance of these stents. The bowel proximal and distal to the stent was gently occluded. A 30cc syringe was then used to inject water into the lumen of the bowel, and the stent-intestine interface was observed for occurrence of leakage.

[0114] Computed tomographic imaging

[0115] High-resolution CT data were acquired on a Philips PrecedenceTM (Brilliance) 16 channel CT imaging system with X-ray tube settings of 90 kVp and 800 mA. With a 100 mm field of view and 0.80 mm slice thickness, the length of the scan was 234 mm. The high-resolution scans were acquired with a collimation of 16x0.75, pitch of 0.313 and a rotation time of 1 .5 sec. 3D stent models were generated based on the measured small intestine dimensions.

[0116] To aid in identification of the stents, a single metallic surgical clip can be placed on either end of the implanted stent (Fig. 12). Stent implantation site can be marked by the use of surgical clips on the parietal surface of the bowel during stent fixation.

[0117] Feasibility of Deploying an Image-guided Prototyped Stent in vivo in a Swine Small Intestine.

[0118] A preliminary live animal study was conducted in 2 pigs to assess the feasibility of placing the stents under a protocol approved by the institutional IACUC (protocol number 17054). One week prior to surgery, each pig was sedated and had abdominal CT imaging performed. The maximum small intestinal diameter was used for a maximum stent diameter that could be tolerated, and corresponding 3D cylindrical tube models for individual stents were produced using CAD software followed by their 3D printing. A maximum small intestinal diameter was obtained by capturing both the maximum outer small intestinal diameter and the maximum inner small intestinal diameter and obtaining an average measurement, which was called the “maximum diameter.” One animal was used as a control, in which the stent dimensions generated were smaller than the maximum small intestinal diameter dimensions determined by imaging, and the other animal was used as the experimental animal, in which the stent dimensions more closely matched those of the animal. A cylindrical stent with a length of 1 cm and thickness of 1 mm was printed for each animal.

[0119] Before the surgical procedure, the animals were fasted overnight. On the day of the procedure, the animals were anesthetized with dexmedetomidine 25 meg kg ¹ , ketamine 10 mg kg ¹ , morphine 0.5mg kg ¹ and midazolam 0.2 mg kg ¹. The pigs were intubated and anesthesia was maintained with isoflurane in 100% oxygen delivered from an anesthesia machine. Following standard aseptic preparation, a midline celiotomy incision was made and the small intestine was accessed. A mid jejunal segment of small intestine was exteriorized and isolated from the abdomen, and a transverse incision was made to allow for insertion of the stent. The enterotomy was closed completely with simple continuous pattern over the stents, and the stents were sutured in place with 4-6 simple interrupted silk sutures engaging the stent and the intestinal wall to prevent stent migration. The enterotomy closure and stent placement segment was leak tested using 12 cc of saline injected into the intestinal lumen. This segment of intestine was then attached to the abdominal wall to the right of midline using sutures between the intestinal wall and the transversus abdominus muscle using 2-0 silk. Routine abdominal closure was performed and the pigs were recovered from anesthesia. In the first 48 hour postoperatively, buprenorphine IM (0.02mg/kg) was given as needed every 6 hours. The pigs were monitored clinically at least twice a day for any evidence of intestinal obstruction or peritonitis, including poor feeding, poor defecation, abdominal distension and vomiting. Animals were euthanized at the end of the 12 weeks monitoring.

[0120] Feasibility of Placing 3D-printed Stents into In Vivo Swine Intestines with Perforation.

[0121] In this cohort of 2 pigs anesthesia and surgery were performed as described previously. Prior to surgery, four curved stents of 1-mm thickness and 5-cm length were 3D-printed. The dimensions for each stent can be found in Table 3. Each end of each stent contained seven to nine evenly-spaced holes. Following exteriorization of a mid- jejunal segment, the surgeon selected the appropriate stent size for each pig based on jejunal size.

[0122] Stent sizing can initially be approximated by measuring the external circumference of the compressed bowel segment. Fig. 13A. An appropriately sized stent, labeled with a metal surgical clip, can be inserted in the enterotomy in the bowel. Fig. 13B. At both the proximal and distal ends, a stent can be sutured to the bowel with 6-8 simple interrupted sutures through the small intestine wall using the pre existing suture holes in the stent. Fig. 13C. A surgical clip can sutured to the exterior of the bowel during stent fixation to aid in identifying enterotomy site in CT scans. The enterotomy can be sutured closed following stent placement. Preliminary studies left a 1 .0 to 1 .5 cm opening in the enterotomy to examine the stent’s ability to isolate the enterotomy site from the lumen of the bowel.

[0123] A transverse enterotomy was performed and the stent was inserted into the jejunal lumen. The enterotomy was closed through apposition of the jejunum over the central area of the stent with two simple continuous suture lines. A 1-cm defect was left in the antimesenteric surface replicating an intestinal perforation where intestinal contents would leak from. The stents were sutured into place via the 3D-printed suture holes using simple interrupted sutures of PDS. The stents were then tested to ensure leakage would not occur. Saline was injected into the intestine at one end of the stent and allowed to flow through the stent and out from the other side. The stent, 1-cm defect, and intestine were closely examined to ensure that they did not exhibit any leakage. The pigs were closed and recovered as previously described for a period of two weeks. At 2 weeks post-operatively the pigs were euthanized and evaluated by necropsy examination.

[0124] Table 3. Curved Stent Dimensions

[0125] Pigs were held off feed the morning of planned radiographs and sedated with midazolam 0.2mg/kg IM and dexmedetomidine 0.02mg/kg IM or Telazol 2mg/kg and Ketamine 0.5mg/kg and Xylazine 50kg/kg IV and abdominal radiographs were performed. Radiographs were performed every week to monitor the integrity and any transit of the stents (through appearance of radiopaque fiducials (vascular clips)) as well as any radiographic evidence of bowel obstruction or perforation. Furthermore, all animals were monitored clinically at least twice a day for five days for any evidence of obstruction, septic peritonitis or other gastrointestinal complications, including poor appetite, poor defecation, and vomiting. During this time the animals were housed in the University of Illinois Veterinary Teaching Hospital Large Animal Clinic. Following their recovery after five days they were returned to the Veterinary Medical Research Farm where they received daily monitoring for the remaining period of two weeks for obstruction or gastrointestinal complications, including poor appetite, poor defecation, and vomiting or diarrhea. Blood and urine samples (2 ml each) were collected from experimental animals every seven days to assess for complications resulting from the intervention. Routine swine blood collection protocol was used involving placement of a typical cable snare over the maxilla of the pig and using a 20G 1 .5" needle inserted into the jugular vein or anterior vena cava utilizing a routine method. The concept and inspiration for personalized absorbable gastrointestinal stents is shown in Fig. 1.

[0126] Statistical Analysis [0127] All statistical testing was conducted using a student’s T-test with unequal variances.

[0128] Results

[0129] Dynamic Mechanical Analysis (DMA)

[0130] Representative stress-strain curves for film samples of each composition are given in Fig. 2A. Based on these curves, the modulus of elasticity (Fig. 2B) is found to increase with PDO content in the PCL: PDO composites. PDO alone exhibits a slightly lower modulus than the 25:75 PCL: PDO ratio, but this is not statistically significant. The yield strength (Fig. 2C) of the 25:75 PCL: PDO composition was found to be lower than that of the 75:25 PCL: PDO composition. Despite this, the 25:75 PCL: PDO ratio has a high yield strength of approximately 2 MPa. As a result, the 25:75 PCL: PDO ratio was chosen for further analysis.

[0131] Representative stress-strain curves and calculated moduli of elasticity for 25:75 PCL: PDO filaments are shown in Fig. 2 D-E. The 25:75 PCL: PDO composite was found to have a slight increase in modulus of elasticity as a result of filament formation. This was likely due to a reduction in composite porosity as a result of filament formation. The presence of pores in a sample would lead to a true cross- sectional area that is lower than the actual cross-sectional area, leading to a lower calculated stress than the true stress value. The increase in temperature from room temperature to physiological temperature did not lead to any statistically significant change in the modulus of elasticity. This indicates that the 25:75 PCL: PDO composite is suitable for physiological applications.

[0132] Computer Aided Design (CAD) and Finite Element Analysis (FEA) [0133] Finite element analysis was conducted for 3 different designs (Fig. 3). The cylindrical design was a simple thin-walled cylinder with a constant inner and outer diameter. The reinforced cylindrical design incorporated rims at the two ends of the stent. These rims would double the thickness in the rimmed areas compared to the un rimmed areas, while the inner diameter remained unchanged. The third design was a curved design, in which both the inner and outer diameters increased from their minimum values at the center of the stent to their maximum values at the two ends of the stent, with the thickness remaining constant throughout. A length of 60 mm and a minimum outer diameter of 30 mm were maintained for all designs. Four different stent thicknesses were evaluated for each design (1 mm, 0.75 mm, 0.5 mm, 0.25 mm). Numerical results for maximum deformation and maximum stress are provided in Table 4 and Table 5 respectively.

[0134] Table 4. Maximum Deformation for Each FEA Model

[0135] Table 5. Maximum Stress for each FEA model

[0136] Scanning Electron Microscopy and FT-IR

[0137] SEM images of the film samples showed a surface with concave features containing some pores and uniform mixing of the polymer (Fig. 4A). This further suggests that the increase in modulus of elasticity of the composite during filament formation may have been caused by a change in porosity.

[0138] FT-IR was used to confirm the presence of both PCL and PDO in the composite and filament (Fig. 4B). The sharp peak near 1720 cm^-1 in PCL and 1735 cm^-1 in PDO can be attributed to the C=0 from the ester bonds in these polymers. The presence of sharp peaks in this range for both the PCL: PDO composite and PCL: PDO filament indicate that the ester bonds were preserved after composite and filament formation. This is significant because the degradation mechanism for these polymers is the hydrolysis of their ester bonds.

[0139] Degradation

[0140] Stent samples incubated with SIF or FBS exhibited a steady loss of mass with time (Fig. 4C). The stent segments experienced an approximately 20% loss of mass to 80% ± 6.4 % (SIF) and 79.6 % ± 11 % (FBS) of their initial mass after 20 days. The slow degradation of the stents is essential to allowing for the full healing of the intestine prior to complete degradation of the stents. Premature degradation of the stents prior to intestinal healing could potentially allow for the occurrence of leakage of intestinal contents, leading to sepsis and other complications. FT-IR spectra of SIF, FBS, and SIF and FBS used for stent degradation display increases in peak intensity or the appearance of new peaks in the range of 800-1000 cm ¹ after stent degradation, potentially corresponding to the presence of some PCL-PDO in the solutions as a result of stent degradation. In SIF samples in particular, there are some apparent shifts in the location of peaks in the 1000-2000 cm ¹ range. Identification of the origin of specific peaks for these samples is beyond the scope of this work as FBS and SIF are both highly complex samples composed of a variety of proteins and enzymes.

[0141] Cell Viability, Proliferation, and Adhesion

[0142] Cell Viability

[0143] When exposed to a low mass (10 mg) of the materials, human intestinal cells did not show any significant change in metabolic activity (Fig. 5A). However, when exposed to a higher mass (100 mg) of the materials, the PCL, PDO, and composite all appeared to induce a reduction in cell metabolic activity, indicating possible cytotoxic effects. Despite this, the filament was still found to have cell metabolic activity that was comparable to the control, even at the higher dose. An increase in material dose was also found to lead to decreases in cell density and morphological deformations for cells exposed to PCL, PDO, and the composite. These adverse effects were not observed in the control cells or the cells exposed to the filament.

[0144] The low cytotoxicity of the filament compared to the raw materials and composite may have been due to the high temperature exerted on the material during the filament extrusion process, which may have led to the death of contaminants that existed in the raw materials or composite. This low cytotoxicity may have also been caused by a difference in the materials’ surface area exposed to the cells, which may have varied as a result of shape, with the filament having a cylindrical shape while the composite has a porous surface, and the PCL and PDO taking the form of beads and pellets respectively. The materials themselves did not show a change in mass after exposure to the cells (Fig. 5B), indicating that cells were not seeded within the material surface.

[0145] Cell Proliferation

[0146] The filament was found to be conducive to cell proliferation over a period of 3 days, while PCL and PDO alone were not (Fig. 5C). For the filament, cell proliferation was found to increase with dose. PCL and PDO alone were found to cause a reduction in cell proliferation. These results suggest that the filament can provide a surface on which cells can grow and proliferate, potentially aiding in healing the intestinal segments after stent placement. Despite providing a surface that was conducive to cell growth, the filament did not show any significant changes in weight after exposure to the cells (Fig. 5D), indicating that the cellular material did not penetrate the samples, and was easily removed via washing of the samples.

[0147] Cell Adhesion

[0148] Cells were found to adhere to the stent surface, even just 14 h after cells were seeded on top of the stent surface (Fig. 5E). This indicates that the stent surface provides an environment on which the intestine can be repaired. The side of the stent not seeded with cells was used as a control for imaging, and did not exhibit any adhesion of cell-like structures.

[0149] Blood Smear

[0150] The exposure of blood to the polymers, composite, and filament did not appear to cause any adverse effects in red blood cell morphology (Fig. 6). This indicates that these materials will not lead to adverse effects when interacting with blood at the surgical site. Images primarily depicted red blood cells rather than lymphocytes, as blood has a higher concentration of red blood cells than lymphocytes. [0151 ] Ex Vivo Placement

[0152] The ease of placement for cylindrical, cylindrical reinforced, and curved stent designs with incorporated suture holes was evaluated ex vivo. The curved design (Fig. 7) was found to be the easiest to place without experiencing slipping of the intestinal segments. The curvature in this design can potentially allow for a secure fit which may reduce risk of passage of intestinal contents between the inside of the intestine and the outside of the stent. The ability of this stent to be sutured in place via the suture holes was also demonstrated. The stent was also shown to retain fluid and prevent leakage when sutured in place within the intestine.

[0153] Feasibility of Deploying an Image-guided Prototyped Stent In Vivo in a Swine Small Intestine.

[0154] CT images (Fig. 8) were utilized to determine the diameter of cylindrical stents utilized in in vivo experiments (Fig. 9). The successful completion of the surgical procedure demonstrated the feasibility of intestine measurement and stent placement. The control animal, who had the undersized stent, showed signs of intestinal obstruction within a few days of stent placement and was sacrificed to prevent further suffering of the animal. The experimental pig did not show symptoms of complication and was sacrificed two weeks after stent placement as described by the protocol. Histological results (Table 6) did not appear to show significant negative effects as a result of stent placement, but histological analysis of tissues from an untreated control animal would be required for an accurate determination of the cause of any histological abnormalities.

[0155] Table 6. Histology Results

[0156] Feasibility of Placing 3D-printed Stents into In Vivo Swine Intestines with Perforation.

[0157] Two pigs were used to trial placement of stents without complete closure of the enterotomy used to place the stent (Fig. 10). These two pigs tolerated the surgical procedure well, however after surgery one pig did not feed well and appeared to have an infection. Necropsy results demonstrated an obstruction within the stent. The small bowel proximal to the obstructed stent was very dilated, which allowed intestinal contents to leak around the stent and through the enterotomy. The bowel in this area was congested and consistent with intra-abdominal infection. The other pig did well following surgery, and was sacrificed as described by protocol. This pig also underwent necropsy. The stent in this pig had been dislodged into the distal jejunum, and was also partially obstructed by ingested materials. The site of the enterotomy did not show sign of leak, but appeared to be adherent to the abdominal wall.

[0158] These results demonstrate the feasibility and utility of the proposed stent fabrication and deployment methods, although some adverse effects did arise from the placement of these stents. A stent that is slightly larger than the intestine may prevent the occurrence of obstructions by allowing for the passage of larger objects through the intestines. Additionally, the occurrence of obstructions would likely have been prevented if the pigs were placed on liquid diets following surgery.

[0159] The presence of the hydrolysable ester bond in FT-IR spectra suggests that the composite retains its biodegradability even after filament formation, and this was confirmed through in vitro degradation experiments.

[0160] Additional Experiments

[0161 ] In vivo experiments in pigs demonstrated the feasibility of using dimensions derived from CT images as a basis for stent fabrication, as well as the feasibility of stent placement via the proposed method. The efficacy of PDO/PCL stents to protect repairs made in the small bowel was tested in a study of 4 pigs (Fig. 11). A 2.0 cm surgical enterotomy was made in the small bowel of 4 individual swine. 3D printed gastrointestinal stents (Fig. 11 A) were sized and inserted into the bowel and sutured to the bowel wall on both ends (Fig. 11 B). Sutures were placed in the periphery of the enterotomy leaving a 1 cm opening in the center. Animals were revived and monitored for 16 days with a CT scan performed on day 6. Necropsy was performed on day 16 and tissues were analyzed by histology. All 4 animals survived to the termination of the experiment. All animals ate and drank normally during the post-surgery period (Fig. 11 C). CT scans at day 6 showed no migration of any stents and no signs of intestinal inflammation. One animal spiked a fever on day 10 and during necropsy it was determined that the stent had migrated approximately 1 cm down the bowel. Even though the enterotomy was left with a 1 cm opening, all animals showed healing of the open enterotomy signifying protection of the incision fora period long enough to permit healing (Fig. 11D). Ex vivo placement of various stent designs indicated the ease of placement of the curved stent design, as well as the use of suture holes for stent placement. The ability of the stent and intestine combination to retain liquid showed the promising potential of these stents to one day serve as a barrier to gastrointestinal tract leakage post-surgery. In a healthy pig model of stent implantation using stents with a 1 .0 mm thickness, significant healing at the site of enterotomy is seen at day 16 post-implantation (Fig. 11).

[0162] Fig. 15 shows histology of intestinal enterotomy region approximately two weeks after stent implantation. Fig. 15A shows 15 X magnification of the enterotomy region showing bridging of the enterotomy with connective tissue (arrows). Fig. 15B shows the region in Fig. 15A delineated by the red box viewed at 100X magnification showing intestinal epithelium forming on the surface of the tissue bridging the enterotomy.

[0163] The degradation of bioresorbable stents were measured and optimized in long-term studies in a pig model. Based on initial in vitro study data, approximately 20% of stent mass is lost over the course of 20 days under physiological temperatures and simulated intestinal fluid. In a healthy pig model of stent implantation using stents with a 1 .0 mm thickness, significant healing at the site of enterotomy is seen at day 16 post-implantation (Fig. 11).

[0164] Stents were examined by Scanning Electron Microscopy (SEM) to characterize degradation and to visualize biofilm on stent (Fig. 4A and Fig. 14). Fig. 14 shows a stent removed 2 weeks after implantation analyzed by SEM. Cracks show beginnings of structural degradation.

[0165] Conclusions

[0166] PCL: PDO composites with varying ratios of PCL and PDO were prepared and characterized. Film samples made of the 25:75 PCL: PDO ratio were found to display the highest modulus of elasticity, and this ratio was selected for further experiments. Filament samples of the 25:75 PCL: PDO ratio were found to have a modulus of elasticity of approximately 211 MPa, with filaments exhibiting a slightly higher modulus of elasticity than the film samples. SEM images showing the porous surface structure of the film samples suggest a change in porosity during the filament extrusion process as a possible cause of the increase in modulus of elasticity. The presence of the ester C=0 bond within the filament indicates retention of the hydrolysable ester bond which is essential to composite degradation. In vitro degradation experiments determined that stent samples had an approximately 20% mass loss over a period of 20 days. Finite element analysis was conducted with cylindrical, reinforced cylindrical, and curved designs with a range of stent thicknesses. A decrease in stent thickness was found to lead to an increase in the stress and deformation experienced by the stent. Despite this, the largest stress experienced by any stent was found to be less than 0.4 MPa, well below the yield strength of the material. The maximum deformation experienced in FEA models was less than 0.02 mm, and the location of this maximum deformation was found to vary based on stent design.

[0167] At a high dose, PCL and PDO alone were found to have adverse effects on cell viability over a period of 48 hours, leading to alteration of cell morphology and a reduction in cell density. The composite and filament samples were found to have no negative impact on cell viability at the low dose, and the filament samples were found to have no negative impact on cell viability even at the higher dose. This suggests that the temperature used in the filament extrusion process may have contributed to material sterility. Further experiments conducted over a period of three days found that the filament provided a surface that was conducive to cell growth, leading to an increase in cell proliferation for both low and high doses. Cells exhibited adhesion to 3D-printed stent samples as few as 14 hours after exposure of cells to the stents. Blood smear testing showed no morphological changes in red blood cells as a result of exposure to the materials, suggesting the safety of material exposure to blood at the surgical site.

[0168] In vivo experiments in pigs demonstrated the feasibility of using dimensions derived from CT images as a basis for stent fabrication, as well as the feasibility of stent placement. The intestinal obstructions observed in the in vivo experiments reinforce the importance of using custom-made stents for each patient. Ex vivo placement of various stent designs indicated the ease of placement of stent designs, including a curved design, as well as the use of suture holes for stent placement. The ability of the stent and intestine combination to retain liquid showed the use of these stents to serve as a barrier to gastrointestinal tract leakage post-surgery.

Claims

CLAIMS We claim:

1. A personalized, bioresorbable, polymeric stent for placement in a body conduit.

2. The personalized, bioresorbable, polymeric stent of claim 1 , wherein the stent is made up of polymer comprising one or more of glycolic acid, lactic acid, 1 ,4- dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, e-caprolactone; polyglycolic acid; polylactic acid; polydioxanone; polycaprolactone; poly(lactide-co- caprolactone); poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoates; polyester; polycarbonate; tyrosine polycarbonate; polyamide; polypeptide; poly(amino acid); polyester; polyesteramide; poly(alkylene alkylate); polyether; polyethylene glycol; polyvinyl pyrrolidone; polyurethane; polyetherester; polyacetal; polycyanoacrylate; poly(oxyethylene)/polyoxypropylene) copolymer; polyacetal; polyketal; polyphosphate; polyphosphoester; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid); silk; chitin; chitosan; polysaccharide; and poly-4-hydroxybutyrate.

3. The personalized, bioresorbable, polymeric stent of claim 2, wherein the stent is made up of a polymer comprising polydioxanone and polycaprolactone.

4. The personalized, bioresorbable, polymeric stent of claim 2, wherein polydioxanone and polycaprolactone are present in a ratio of about 10:90, 20:80, 25:75; 30:70, or 50:50.

5. The personalized, bioresorbable, polymeric stent of claim 1 , wherein the stent is in a shape of a cylinder with a central bore.

6. The personalized, bioresorbable, polymeric stent of claim 1 , wherein the stent has a thickness of about 0.5, 0.75, 1.0, 1 .25, 1.5 mm or more.

7. The personalized, bioresorbable, polymeric stent of claim 1 , wherein the stent is about 0.1 , 0.5, 1.0, 2.5, 5, 0, 7.5, 10, 15, 20, 25, 30, 40, 45, 50, 60, 70, 80, 100 mm or more in length.

8. The personalized, bioresorbable, polymeric stent of claim 1 , wherein an inner diameter of the stent is about 1 .0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 5,0, 6.0, 7,0, 8.0, 9.0, 10.0 cm or more.

9. The personalized, bioresorbable, polymeric stent of claim 1 , wherein an inner diameter of the stent is about 1 .75 to about 3.5 cm.

10. The personalized, bioresorbable, polymeric stent of claim 1 , wherein 2, 3, 4,

5, 6, 7, 8, 10 or more suture holes are present in the stent.

11. The personalized, bioresorbable, polymeric stent of claim 5, wherein an outer diameter of the stent is larger at each end of the cylinder as compared to the outer diameter at a middle of the stent.

12. The personalized, bioresorbable, polymeric stent of claim 11 , wherein an outer diameter of the stent at the ends of the stent are about 0.1 , 0.5, 0.75, 1.0, 1.25 1.5, 1 .75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.75, 4.0, 5.0 or more mm larger than the outer diameter of the stent at the middle of the stent.

13. The personalized, bioresorbable, polymeric stent of claim 5, wherein thicknesses of each end of the cylinder are greater than that of a thickness of a remainder of the cylinder forming thickened rims at each end of the cylinder.

14. The personalized, bioresorbable, polymeric stent of claim 13, wherein the rims of the cylinder are about 0.1 , 0.25, 0.5, 0.75, 1 .0 mm or more thicker than the remainder of the cylinder.

15. The personalized, bioresorbable, polymeric stent of claim 1, wherein the stent is 3D printed.

16. A method of making the personalized, bioresorbable, polymeric stent of claim 1 for a subject comprising:

(a) imaging a body conduit of the subject to form an image of the body conduit;

(b) determining a maximum body conduit diameter from the image; (c) using computer aided design to produce a body conduit design using the maximum body conduit diameter or a larger diameter; and

(d) making the personalized, bioresorbable, polymeric stent using 3D printing.

17. The method of claim 16, wherein the personalized, bioresorbable, polymeric stent has a diameter of 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1.25, 1.5, 1.75, 2.0, 3.0, 4.0, 5.0 mm or more larger than the maximum body conduit diameter.

18. The method of claim 16, wherein the personalized, bioresorbable, polymeric stent has a diameter 0.01 % to 5% larger than the maximum body conduit diameter.

19. A method of implanting a personalized, bioresorbable, polymeric stent in a subject comprising:

(a) preparing a body conduit in a subject for implantation by creating a first end and a second end of the body conduit;

(b) inserting the stent of claim 1 into the first end of the body conduit and into the second end of the body conduit so that at least part of the first end of the body conduit covers at least a portion of a first end of the stent and at least a portion of the second end of the body conduit covers at least a portion of a second end of the stent; and

(c) suturing the stent to the body conduit.

20. The method of claim 19, wherein the body conduit is an esophagus, a trachea an urethra, a large intestine, or a small intestine.

21. The method of claim 19, wherein the stent is formed by:

(a) imaging a body conduit of the subject to form an image of the body conduit;

(b) determining a maximum body conduit diameter from the image;

(c) using computer aided design to produce a body conduit design using the maximum body conduit diameter or a larger diameter; and (d) making a personalized, bioresorable polymeric stent based on the body conduit design using 3D printing.

22. The method of claim 19, wherein the first end of the body conduit covers the first end of the stent and the second end of the body conduit covers the second end of the stent, such that the first end of the body conduit is in contact with the second end of the body conduit, such that the stent is covered by both the first and second ends of the body conduit.

23. The method of claim 19, wherein the stent is bioresorbed by the subject and does not need to be removed from the subject.

24. The method of claim 19, wherein the subject is a mammal.

25. The method of claim 19, wherein the personalized, bioresorbable, polymeric stent has a diameter of 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1.25, 1.5, 1.75, 2.0. 3.0, 4.0, 5.0 mm or more larger than the maximum body conduit diameter.

26. The method of claim 19, wherein the personalized, bioresorbable, polymeric stent has a diameter 0.01 % to 5% larger than the maximum body conduit diameter.