ASSESSING THE RESPONSE TO TREATMENT OF SINUSITIS

Abstract

This disclosure describes, inter alia, materials, devices, kits and methods that may be used to treat chronic sinusitis, including method for assessing sinonasal protein and mRNA markers as an indicator of a positive therapeutic response to treatment.

Claims

1. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) assessing the concentration of one or more sinonasal Type 2 proteins in said patient, said proteins selected from the group consisting of type 2 markers IL-13, CCL26 and Periostin.

2. The method of claim 1, wherein said method further comprises providing a second implant, and implanting said second implant into said middle meatus area of said second nasal cavity so as to create an implanted second implant in said patient on the opposite nasal cavity of said first implant, wherein said second implant comprises a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said second implant configured to release said mometasone furoate for more than 12 weeks, wherein said second implant is configured to fit into said middle meatus area.

3. The method of claim 1, wherein said assessing of step c) is done over time.

4. The method of claim 1, wherein said assessing of step c) is done at different time points.

5. The method of claim 1, wherein the protein concentrations at different time points are compared to the protein concentrations obtained at a starting point, said starting point selected from the group consisting of just prior, just after and at the time of the implanting of step b).

6. The method of claim 1, wherein said implanted first implant releases a daily dose of said mometasone furoate to surrounding tissues.

7. The method of claim 5, wherein the concentration of one or more sinonasal Type 2 proteins is found to be reduced when compared to the concentration measured at said starting point.

8. The method of claim 7, wherein said reduced concentration is indicative of a positive therapeutic response to the implant.

9. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) assessing the mRNA level of one or more sinonasal Type 2 markers of said patient, said markers selected from the group consisting of type 2 markers CLC, CCL26 and Periostin.

10. The method of claim 9, wherein said method further comprises providing a second implant, and implanting said second implant into said middle meatus area of said second nasal cavity so as to create an implanted second implant in said patient on the opposite nasal cavity of said first implant, wherein said second implant comprises a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said second implant configured to release said mometasone furoate for more than 12 weeks, wherein said second implant is configured to fit into said middle meatus area.

11. The method of claim 9, wherein said assessing of step c) is done over time.

12. The method of claim 9, wherein said assessing of step c) is done at different time points.

13. The method of claim 9, wherein the mRNA levels at different time points are compared to the mRNA levels obtained at a starting point, said starting point selected from the group consisting of just prior, just after and at the time of the implanting of step b).

14. The method of claim 9, wherein said implanted first implant releases a daily dose of said mometasone furoate to surrounding tissues.

15. The method of claim 13, wherein the level of one or more sinonasal Type 2 mRNA markers is found to be reduced when compared to the mRNA level measured at said starting point.

16. The method of claim 15, wherein said reduced level is indicative of a positive therapeutic response to the implant.

17. The method of claim 15, wherein said assessing is done by taking a nasal swab and performing RT-PCR.

18. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) detecting a reduction in the concentration of a CCL26 sinonasal Type 2 protein, said reduction being at least four-fold in said patient within four (4) weeks after said implanting.

19. The method of claim 18, wherein said method further comprises providing a second implant, and implanting said second implant into said middle meatus area of said second nasal cavity so as to create an implanted second implant in said patient on the opposite nasal cavity of said first implant, wherein said second implant comprises a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said second implant configured to release said mometasone furoate for more than 12 weeks, wherein said second implant is configured to fit into said middle meatus area.

20. The method of claim 18, wherein said detecting of step c) is done over time.

21. The method of claim 18, wherein said detecting of step c) is done at different time points.

22. The method of claim 1, wherein the CCL26 protein concentration at different time points is compared to the CCL26 protein concentration obtained at a starting point, said starting point selected from the group consisting of just prior, just after and at the time of the implanting of step b).

23. The method of claim 1, wherein said implanted first implant releases a daily dose of said mometasone furoate to surrounding tissues.

24. The method of claim 22, wherein the concentration of the CCL26 sinonasal Type 2 protein is found to be reduced when compared to the CCL26 concentration measured at said starting point.

25. The method of claim 18, wherein said reduced CCL26 protein concentration is indicative of a positive therapeutic response to the implant.

26. The method of claim 18, wherein said detecting said CCL26 protein level is done by taking a nasal swab and performing an immunoassay.

27. The method of claim 18, wherein said chronic sinus condition is chronic rhinosinusitis.

28. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) detecting a reduction in the mRNA level of a CCL26 sinonasal Type 2 marker, said reduction being at least two-fold in said patient within four (4) weeks after said implanting.

29. The method of claim 28, wherein said method further comprises providing a second implant, and implanting said second implant into said middle meatus area of said second nasal cavity so as to create an implanted second implant in said patient on the opposite nasal cavity of said first implant, wherein said second implant comprises a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said second implant configured to release said mometasone furoate for more than 12 weeks, wherein said second implant is configured to fit into said middle meatus area.

30. The method of claim 28, wherein said detecting of step c) is done over time.

31. The method of claim 28, wherein said detecting of step c) is done at different time points.

32. The method of claim 28, wherein the CCL26 mRNA level at different time points is compared to the CCL26 mRNA level obtained at a starting point, said starting point selected from the group consisting of just prior, just after and at the time of the implanting of step b).

33. The method of claim 28, wherein said implanted first implant releases a daily dose of said mometasone furoate to surrounding tissues.

34. The method of claim 32, wherein the level of the CCL26 Type 2 mRNA marker is found to be reduced when compared to the CCL26 mRNA level measured at said starting point.

35. The method of claim 34, wherein said reduced CCL26 mRNA level is indicative of a positive therapeutic response to the implant.

36. The method of claim 28, wherein said detecting said CCL26 mRNA level is done by taking a nasal swab and performing RT-PCR.

37. The method of claim 28, wherein said chronic sinus condition is chronic rhinosinusitis.

38. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) assessing the concentration of one or more sinonasal Type 2 proteins in said patient, said proteins selected from the group consisting of type 2 markers CCL26 and Periostin, wherein when the concentration of one or more sinonasal Type 2 proteins is found to be reduced when compared to the concentration measured at a starting point, said reduced concentration is indicative of a positive therapeutic response to the implant.

39. A method of treatment, comprising: a) providing, i) a human patient having first and second nasal cavities, each comprising a middle meatus area, wherein said patient has at least two symptoms of a chronic sinus condition; ii) a first implant comprising a therapeutic-agent formulation containing layer comprising over 2000 micrograms of mometasone furoate, said first implant configured to release said mometasone furoate for more than 12 weeks, wherein said first implant is configured to fit into said middle meatus area; b) implanting said first implant into said middle meatus area of said first nasal cavity so as to create an implanted first implant; c) assessing the mRNA level of one or more sinonasal Type 2 markers, said markers selected from the group consisting of type 2 markers CCL26 and Periostin, wherein when the level of one or more Type 2 mRNA markers is found to be reduced when compared to the mRNA level measured at a starting point, said reduced level is indicative of a positive therapeutic response to the implant.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0374] Some of the accompanying figures are schematic and not intended to necessarily be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0375] FIG. 1A schematically illustrates various fiber cross-sections, in accordance with embodiments of the present disclosure.

[0376] FIG. 1B schematically illustrates multi-fiber filament cross-sections, in accordance with two embodiments of the present disclosure.

[0377] FIG. 2 is a schematic side view of a self-expanding scaffold, in accordance with an embodiment of the present disclosure.

[0378] FIG. 3A is a schematic side view of a self-expanding scaffold having uniform braid angles, in accordance with an embodiment of the present disclosure.

[0379] FIG. 3B is a schematic side view of a self-expanding scaffold having variable braid angles, in accordance with an embodiment of the present disclosure.

[0380] FIG. 4 is a schematic side view of a self-expanding scaffold having an elastomer coating, in accordance with an embodiment of the present disclosure.

[0381] FIG. 5 is a schematic side view of a self-expanding scaffold having an elastic cross-fiber, in accordance with an embodiment of the present disclosure.

[0382] FIG. 6A is a schematic side view of a self-expanding scaffold having filaments of different stiffness, in accordance with an embodiment of the present disclosure.

[0383] FIG. 6B is a schematic side view of a self-expanding scaffold having removed filament segments, in accordance with an embodiment of the present disclosure.

[0384] FIG. 6C is a schematic side view of a self-expanding scaffold having coated ends, in accordance with an embodiment of the present disclosure.

[0385] FIG. 6D is a schematic side view of a self-expanding scaffold having alternating coated and uncoated sections, in accordance with an embodiment of the present disclosure.

[0386] FIG. 7 is a photograph of a self-expanding scaffold having unequal cell sizes, in accordance with an embodiment of the present disclosure.

[0387] FIG. 8 is a schematic side view of a self-expanding scaffold having fold-back ends, in accordance with an embodiment of the present disclosure.

[0388] FIG. 9 is an illustration of a knitted scaffold, in accordance with an embodiment of the present disclosure.

[0389] FIG. 10 is a schematic perspective view of a spiral-shaped self-expanding scaffold, in accordance with an embodiment of the present disclosure.

[0390] FIG. 11A is a photograph of a spiral-shaped self-expanding scaffold formed from a braided tubular scaffold, in accordance with an embodiment of the present disclosure.

[0391] FIG. 11B is a photograph of a spiral-shaped self-expanding scaffold formed from a two-carrier braid, in accordance with an embodiment of the present disclosure.

[0392] FIG. 12A is a schematic perspective view of a self-expanding scaffold having solid strut hoops, in accordance with an embodiment of the present disclosure.

[0393] FIG. 12B is a schematic perspective view of a self-expanding scaffold having strut hoops in the form of a two carrier braid design, in accordance with an embodiment of the present disclosure.

[0394] FIG. 13 is a schematic side view of a conformal tube, in accordance with an embodiment of the present disclosure.

[0395] FIG. 14A is a schematic perspective view of a conformal tube with an associated three-dimensional support structure in expanded form, in accordance with an embodiment of the present disclosure.

[0396] FIG. 14B is a schematic end view of a conformal tube with an associated three-dimensional support structure in crimped form, in accordance with an embodiment of the present disclosure.

[0397] FIG. 15 is a schematic side view of a scaffold in the form of a unitary polymeric structure, in accordance with an embodiment of the present disclosure.

[0398] FIG. 16 is a photograph of an 8 mm diameter scaffold, a 10 mm diameter scaffold, a 20 mm diameter scaffold and a 31 mm diameter scaffold, each with 16 strands, in accordance with embodiments of the present disclosure.

[0399] FIG. 17A is a graph illustrating cumulative absolute mass of mometasone furoate (MF) released in the presence of poly(lactic acid-co-caprolactone) (PLCL) as the drug carrier polymer as a function of time for three different drug loadings, in accordance with embodiments of the present disclosure.

[0400] FIG. 17B is a graph illustrating cumulative percent mass of MF released in the presence of PLCL as the drug carrier polymer as a function of time for the embodiments of FIG. 17A.

[0401] FIG. 18 is a graph illustrating cumulative percent mass of MF released in the presence of PLCL as the drug carrier polymer, with and without a topcoat comprising PLCL and PLA, as a function of time for one 400 μg MF scaffold with no topcoat and three 400 μg MF scaffolds with different topcoat thicknesses, in accordance with embodiments of the present disclosure.

[0402] FIG. 19 is a graph illustrating cumulative percent mass of MF released in the presence of D,L-PLGA as the drug carrier polymer as a function of time for 400 μg MF scaffolds containing three different types of D,L-PLGA, in accordance with embodiments of the present disclosure.

[0403] FIG. 20A is a photograph of a 31.75 mm scaffold with 16 strands, in accordance with an embodiment of the present disclosure.

[0404] FIG. 20B is a photograph of a coated node of a scaffold like that of FIG. 20A.

[0405] FIG. 21 is a graph illustrating compressive load versus compressive strain for a scaffold in accordance with an embodiment of the present disclosure.

[0406] FIGS. 22A-22E are photographs illustrating various scaffold designs, in accordance with various embodiments of the present disclosure.

[0407] FIG. 23A, FIG. 23B, FIG. 23C and FIG. 23D are photographs illustrating deployment in a swine nasal cavity of a scaffold in accordance with an embodiment of the present disclosure.

[0408] FIG. 24 is a photograph illustrating a scaffold in accordance with an embodiment of the present disclosure following deployment in a swine nasal cavity.

[0409] FIG. 25 is a photograph illustrating a 32 filament scaffold having a diameter of 13 mm diameter and a length of 10 mm, in accordance with an embodiment of the present disclosure, following deployment in the native middle meatus of a human cadaver.

[0410] FIG. 26 is a photograph illustrating a 16 filament, 10 mm scaffold in accordance with an embodiment of the present disclosure following deployment in the frontal sinus ostia of a human cadaver.

[0411] FIG. 27 is a photograph illustrating a 32 filament scaffold having a diameter of 17.5 mm and a length of 10 mm, in accordance with an embodiment of the present disclosure, following deployment in the ethmoid sinus of a human cadaver following FESS.

[0412] FIGS. 28A-28D are optical microscopic images of coated 8 mm scaffolds having 16 strands with and without anisole as a co-solvent during spray-coating as follows: FIG. 28A, PLGA(10:90) scaffold without anisole co-solvent; FIG. 28B, PLGA(10:90) scaffold with anisole co-solvent; FIG. 28C, PLGA(75:25) scaffold without anisole co-solvent; FIG. 28D PLGA(75:25) with anisole co-solvent.

[0413] FIGS. 29A-29C show optical images of coated scaffolds with and without anisole as a co-solvent during spray-coating as follows: FIG. 29A scaffold coated with 62 wt % elastomer relative to the weight of the base braid from solution without anisole as a co-solvent; FIG. 29B scaffold coated with 63 wt % elastomer from solution containing anisole as a co-solvent; and FIG. 29C scaffold coated with 100 wt % elastomer from solution containing anisole as a co-solvent.

[0414] FIG. 30A illustrates cumulative absolute mass of MF released from three sets of MF-coated scaffolds as a function of time.

[0415] FIG. 30B illustrates cumulative percent mass of MF released from three sets of MF-coated scaffolds as a function of time.

[0416] FIG. 31 illustrates in two drug release profiles of MF-coated PLGA(10:90) scaffolds and MF-coated PLGA(75:25) scaffolds.

[0417] FIG. 32 illustrates MF concentration in the sinus mucosa of sacrificed rabbits as a function of time post-implantation.

[0418] FIG. 33 illustrates total MF in vivo as a function of time (MF on scaffold plus MF in the sinus mucosa of scarified rabbits).

[0419] FIG. 34 illustrates cumulative percent mass of MF released from two sets of MF-coated scaffolds as a function of time.

[0420] FIG. 35 illustrates cumulative percent mass of MF released from four sets of MF-coated scaffolds as a function of time.

[0421] FIG. 36A illustrates immediate recovery from a first amount of compression of two sets of MF-coated scaffolds with 90 and 128 braid angles, as a function of compression time.

[0422] FIG. 36 B illustrates immediate recovery from a second amount of compression of two sets of MF-coated scaffolds with 90 and 128 braid angles, as a function of compression time.

[0423] FIG. 37A illustrates six hour recovery from a first amount of compression of two sets of MF-coated scaffolds with 90 and 128 braid angles, as a function of compression time.

[0424] FIG. 37 B illustrates six hour recovery from a second amount of compression of two sets of MF-coated scaffolds with 90 and 128 braid angles, as a function of compression time.

[0425] FIG. 38 is a schematic illustration of a testing apparatus for conducting compression testing, in accordance with an embodiment of the present disclosure.

[0426] FIG. 39 illustrates cumulative absolute mass of MF released from a set of MF-coated scaffolds as a function of time.

[0427] FIG. 40 illustrates patients showing evidence of symptom improvement by decreasing symptoms measured using a bilateral SNOT-22 Score (Validated scale that measures quality of life on 22 metrics) over time (up to 24 weeks with a 1 week post-removal score for 1 patient). *p<0.05 with paired t-test performed to baseline. Published change from endoscopic surgery: Reference 1. Clin Otolaryngol. 2009 October; 34(5):447-54; Reference 2. JAMA Otolaryngol Head Neck Surg. 2014; 140(8):712-719; Reference 3. Int Forum Allergy Rhinol. 2016; 6:557-567.

[0428] FIG. 41 illustrates a bilateral symptom improvement measurement as a SNOT-22 for each patient at baseline (0) and 3 months (12 weeks). Symptom improvement shown by decreasing Severity of SNOT-22 Score (N=10): at 0 & 12 weeks.

[0429] FIG. 42 illustrates that patient disease severity is decreasing over time by percent (%) of subjects showing decreasing severity of a bilateral SNOT-22 Score over time, from 2 weeks before implantation, up to at least 12 weeks. Severity defined by Toma and Hopkins, Rhinology. 2016 June; 54(2):129-33. SNOT>50 (severe) (orange blocks); SNOT>20-50 (moderate) (gray blocks); SNOT=8-20 (mild) (blue blocks); SNOT<8 (normal) (green blocks).

[0430] FIG. 43 illustrates symptom improvement comparison to existing therapies as bilateral SNOT-22 Score change from baseline. Surgery (blue bar); Optinose NAVIGATE I (orange bar); Optinose NAVIGATE II (gray bar); exemplary 480 scaffold of the present invention (green bar) Superscript 1: N=10, data at 12 weeks; Superscript 2: Hopkins 2009 for surgery data at 3 months; Optinose Piper Initiation 2017, data at 16 weeks (orange bar and gray bar).

[0431] FIG. 44A-B illustrates a bilateral SNOT-22 Score rhinological subdomain (FIG. 44A) and ear-facial subdomain (FIG. 44B) showing significant improvement by up to 4 Weeks. *p<0.05 with paired t-test performed to baseline. FIG. 44A illustrates SNOT-22 Rhinological Subdomain (Maximum Score=30). Subdomain scores change due to Medical treatment=−3.0. Subdomain scores change due to surgical treatment=−8.1. (DeConde. Int Forum Allergy Rhino. 2014, Vol 4, p. 972-79) FIG. 44B illustrates a bilateral SNOT-22 Ear-Facial Dysfunction Subdomain (Maximum Score=25). Change due to Medical treatment=−1.6. Change due to surgical treatment=−4.6. (DeConde. Int Forum Allergy Rhino. 2014, Vol 4, p. 972-79).

[0432] FIG. 45 illustrates significant improvement in three cardinal symptoms per FDA guidance document: Congestion+Discharge+Facial pain. Three cardinal symptoms were monitored up to 24 weeks, including a 25th week as a 1-week post-removal assessment. Maximum score=15. *p<0.05 with paired t-test performed to baseline.

[0433] FIG. 46A illustrates pharmacokinetic clinical data in vivo indicates steady daily dosing through 12 Weeks, as determined from measuring systemic drug concentration in plasma. Plasma Drug Concentration (pg/mL).

[0434] FIG. 46B is a schematic illustration showing comparative types of drug release profiles: first-order-release rates of high drug amounts at the beginning of release that decrease over time (dark orange dots); zero-order drug release rates continuous over time (line of blue squares); and pulsatile release rates as rapid increases and decreases in drug release rates over time (yellow triangles).

[0435] FIG. 46C illustrates data as a projected daily dose in vivo derived form IV-IVC correlation in conjunction with the in vitro release shown in FIG. 39. Plasma drug concentration is linear for over at least a 3-month period or more, indicating a steady (consistent) daily dose, i.e. release rate, of MF over months. For exemplary methods, see, Stjarne, et al., A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis. Arch Otolaryngol Head Neck Surg, 2006. 132(2): p. 179-85 and Giger, et al., Comparison of once-versus twice-daily use of beclomethasone dipropionate aqueous nasal spray in the treatment of allergic and non-allergic chronic rhinosinusitis. Eur Arch Otorhinolaryngol, 2003. 260(3): p. 135-40.

[0436] FIG. 47A illustrates Imaging Analysis: Endoscopy, for a patient treated in a Phase I trial. Imaging analysis by independent MD reviewer, including: Assessment of implant placement; Change in polyp grade; Grading of edema and discharge. Increasing magnification from left (screening, S=septum), middle (4 weeks, MM=middle meatus) and right (12 weeks) (highest magnification). White arrows point to polyps; black arrows point to a scaffold. S-septum and MM middle meatus.

[0437] FIG. 47B illustrates, for reference, a magnified endoscopic view looking into a left (in relation to the patient) nostril, showing a septum (S), a middle turbinate (MT) and a middle meatus (MM).

[0438] FIG. 48 is an illustration showing anatomical labeling, as a colored representation of a Coronal MRI image.

[0439] FIG. 49A-D illustrates exemplary steps for inserting a scaffold into a middle meatus.

[0440] FIG. 49A Exemplary step for inserting of scaffold. Draw the depot into the applicator until the entire depot is visible within the applicator sheath. With appropriate instrument, cut loading assembly about 3 cm from applicator's distal tip (this will release one half of the drawstring sutures).

[0441] FIG. 49B Exemplary step for inserting of scaffold. Hold hub with one hand, and carefully withdraw remaining portion of loading assembly to remove loading sutures from depot.

[0442] FIG. 49C Exemplary step for inserting of scaffold. Carefully remove both the applicator sheath assembly and deployment plunger from the packaging insert. Insert deployment plunger through hole in hub cap.

[0443] FIG. 49D Exemplary step for inserting of scaffold. Advance crimped MFSDD to distal end of the applicator sheath. The product is ready for introduction into the nasal passage.

[0444] FIG. 49E illustrates a partial deployment of the scaffold from the end of the applicator sheath, outside of nose, merely for illustrative purposes.

[0445] FIG. 50 shows graphs indicating that sinonasal proteins of type 2 markers IL-13, CCL26 and Periostin, were suppressed in patients receiving the implant described herein.

[0446] FIG. 51 shows graphs indicating that Sinonasal messenger RNAs of type 2 markers CCL26, Periostin, and CLC, were suppressed in patients receiving the implant described herein.

[0447] FIG. 52 shows Lyra (LYR-210) PK protein swab samples. Received samples=Total 98 protein swabs: 50 D1 (Day 1) samples (24 donors). 48 D56 (Day 56) samples (24 donors). Two D1 protein swabs used for RNA (did not use for protein assays). 48 swabs were from right side of nose: Protein extraction: Add 120 ul Protease inhibitor/PBS. 48 swab samples were used in Luminex assays. Eight Type 2 markers were found based on P1 (phase 1) results using 2 different kits: Millipore high sensitivity kit: IL-4; IL-5; IL-13; IL-21. R&D regular kit: CCL18 (PARC); CCL24 (Eotaxin-2); CCL26 (Eotaxin-3); Periostin.

[0448] FIG. 53A shows Phase 1 Protein swab results. Baseline: N=20; Week 4: N=18; Week 12: N=20. Compared to baseline. * P<0.05 **P<0.01 ***P<0.001.

[0449] FIG. 53B shows phase 1 Protein swab results. CRSsNP and CRSwNP separately.

[0450] FIG. 54A shows PK Study Protein swab assay result with dose assignment (24 pairs). 2500 ug (12 pairs) 7500 ug (12 pairs). 2500 ug (12 pairs) *P<0.05 ** P<0.01

[0451] FIG. 54B shows PK Study Protein swab assay result with dose assignment (24 pairs). 2500 ug (12 pairs) 7500 ug (12 pairs) *P<0.05 ** P<0.01. 7500 ug (12 pairs).

[0452] FIG. 54C shows PK Study Protein swab assay Delta (change) (Day (D)56-Day (D)1).

[0453] FIG. 55 shows a Comparison between Phase 1 and PK 2500 ug dose. Detectability of CCL24, CCL26 and Periostin at baseline was higher in phase 1 samples. * P<0.05 **P<0.01 ***P<0.001

[0454] FIG. 56 shows a Comparison between Phase 1 and PK samples in CRSsNP at Baseline. Phase 1 (n=12) vs PK (n=20) at baseline; PK 2500 ug (n=10) vs PK 7500 ug (n=10) at baseline. Baseline IL-4, CCL24, and Periostin were more elevated in P1 samples. * P<0.05 **P<0.01 ***P<0.001

[0455] FIG. 57A shows a Comparison between Phase 1 and PK samples in CRSsNP. Phase 1 protein swab samples (Week 4: 11 pairs, Week 12: 12 pairs) * P<0.05 *** P<0.01 *** P<0.001

[0456] FIG. 57B shows a Comparison between Phase 1 and PK samples in CRSsNP. PK protein swab samples, 2500 ug (10 pairs. PK protein swab samples, 7500 ug (10 pairs). * P<0.05 *** P<0.01 *** P<0.001

[0457] FIG. 58 shows Protein swab assay issues. 1. There were two types of swabs in protein study. At the site 3, many samples were collected by RNA swab which absorbed a limited amount secretion compared to protein swab. Furthermore, detection of CCL26 and Periostin in swab samples was associated with the use of protein swab at the site 3. CCL18 and CCL24 also showed a similar pattern.

[0458] FIG. 59 shows Protein swab assay issues. 2. All of protein swab samples contained fluid. 32 fluid samples. Left: Example for liquid is <500 ul. Right: Example for liquid is >1000 ul. Concentration of T2 biomarkers in swab samples was positively correlated with fluid samples and concentration in swab samples looked up to 2 fold higher than in fluid samples (16 pairs).

[0459] FIG. 60 shows a Comparison between protein swabs and fluid samples—two doses combined. Fluid samples (16 pairs) *P<0.05 **P<0.01

[0460] FIG. 61 Comparison between Phase 1 and PK samples. Detectability of CCL24, CCL26 and Periostin at baseline was higher in phase 1 samples.* P<0.05 ***P<0.001 ****P<0.0001

[0461] FIG. 62 shows a Comparison between Phase 1 and PK samples in CRSsNP. Phase 1 protein swab samples (Week 4: 11 pairs, Week 12: 12 pairs); and PK protein swab samples (20 pairs)—two doses combined.

[0462] FIG. 63 shows Correlations between protein and RNA swab samples at baseline (n=17).

[0463] FIG. 64A shows that Swabs were different between Phase I and PK study. Left: Phase I Metal swab. Right: PK Non-metal swab.

[0464] FIG. 64B shows RNA swab assays for T2 markers in PK study. PK study plan.

[0465] FIG. 64C shows Phase 1 results. Sinonasal messenger RNAs of type 2 marker, CCL26, Periostin, and CLC, were suppressed by LYR-210. Type 1 markers, CXCL9 and CXCL10, were not affected by LYR-210. Expression of mRNAs in nasal swabs at Baseline (week 0) (n=20), 4 weeks (n=11), and 12 weeks (n=9) were assessed by quantitative RT-PCR. Results show only paired samples at 4 weeks and 12 weeks that met RNA quality test. Gene expression levels are shown as % expression of a housekeeping gene, b-glucuronidase (GUSB). Results are shown as mean±SEM. *** p<0.001 by the Wilcoxon matched-pairs signed rank test.

[0466] FIG. 65 shows RNA swab assay results. Periostin was significantly reduced by LYR-210. IL-21 and CCL18 were significantly enhanced by LYR-210. Log scale. RIN>5, 13 pairs

[0467] FIG. 66 shows RNA swab assay result with dose assignment (all samples, 17 pairs). 2500 ug (12 pairs); 7500 ug (5 pairs).

[0468] FIG. 67 shows RNA swab assay result with dose assignment (all samples, 2500 ug: n=12, 7500 ug: n=5). Delta (D56-D1). Fold (D56/D1). Many samples showed below the detection limit in IL-5, IL-13 and IL-21 and therefore no fold changes shown for these markers.

[0469] FIG. 68 shows a Comparison between Phase 1 and PK samples. Phase 1 (n=20) vs PK (n=17) in all CRS at baseline.

[0470] FIG. 69 shows a Comparison between Phase 1 and PK samples in CRSsNP.

[0471] FIG. 70 shows a Comparison between Phase 1 and PK samples in CRSsNP. Phase 1 (n=12) vs PK (n=14) at baseline.

[0472] FIG. 71 shows a Comparison between Phase 1 and PK samples in CRSsNP.

[0473] FIG. 72 shows a RNA swab assay for additional T2 (T-helper cell type 2 inflammation) markers. CST1 was significantly reduced and SERPINB1 was significantly enhanced by LYR-210. All samples (17 pairs). Dose assignment. Delta=change and Fold=fold change.

[0474] FIG. 73 shows Exemplary considerations by biomarkers—two doses combined. Separated groups by IL-13=0.5.

[0475] FIG. 74 shows Exemplary considerations by biomarkers—two doses combined. Separated groups by Periostin=1000. Periostin was <1000 (n=9). Periostin was >1000 (n=8).

[0476] FIG. 75 shows Exemplary considerations by biomarkers—two doses combined. Separated groups by CST1=1000. CST1 was <1000 (n=8). CST1 was >1000 (n=9).

[0477] FIG. 76 shows RNA swab assay results. Periostin was significantly reduced by LYR-210. IL-21 and CCL18 were significantly enhanced by LYR-210. RIN>5, 13 pairs.

[0478] FIG. 77 shows a Comparison between Phase 1 and PK samples in CRSsNP.

[0479] FIG. 78 shows a RNA swab assay (Correlations). Baseline samples n=17). All samples (n=34).

DEFINITIONS

[0480] The intent is to treat sinusitis without directly treating the sinus itself, i.e. without placing the implant in the sinus cavity.

[0481] “Sinus” in general refers to cavities and their epithelial linings, such as maxillary sinuses, ethmoidal sinuses, and sphenoid sinuses, etc.

[0482] “Ethmoidal sinuses” or “ethmoidal air cells” of the ethmoid bone refer to paired paranasal sinuses, including those found in both anterior and posterior areas of the nasal cavity. Ethmoidal sinuses are variable in both size and number of small cavities between individuals.

[0483] In contrast, although “sphenoid sinuses” are considered paranasal sinuses, as are ethmoidal sinuses, sphenoid sinuses refer to irregular cavities within the body of the sphenoid bone. Sphenoid sinuses are in air communication with nasal cavities.

[0484] “Chronic Sinusitis” refers to having at least two symptoms, including but not limited to: impaired nasal obstruction, congestion, nasal discharge when blowing nose, spontaneous nasal discharge from one or both nostrils, nasal discharge into the throat area, facial pain, facial pressure, facial fullness, headache, olfactory loss, etc.

DETAILED DESCRIPTION

[0485] The implantable medical devices of the present disclosure are generally tubular devices, which devices are self-expanding devices in various embodiments. As used herein, “device,” “scaffold,” “stent”, “carrier” and “implant” may be used synonymously. Also as used herein, “self-expanding” is intended to include devices that are crimped to a reduced delivery configuration for delivery into the body, and thereafter tend to expand to a larger suitable configuration once released from the delivery configuration, either without the aid of any additional expansion devices or with the partial aid of balloon-assisted or similarly-assisted expansion. As used herein, “strength” and “stiffness” may be used synonymously to mean the resistance of the medical scaffolds of the present disclosure to deformation by radial forces or a force applied by the scaffolds against a static abutting object. Examples of strength and stiffness measurements, as used to characterize the medical scaffolds of the present disclosure, include radial resistive force and chronic outward force, as further described herein.

[0486] Scaffolds in accordance with the present disclosure are typically tubular devices which may be of various sizes, including a variety of diameters and lengths, and which may be used for a variety of sinus applications. In the case of objects of non-circular cross-section, “diameter” denotes width. In certain beneficial embodiments, the as-manufactured (or unconstrained) diameter of the scaffold may range from 5 mm or less to 60 mm or more, for example, ranging from 5 mm to 10 mm to 15 mm to 20 mm to 25 mm to 30 mm to 35 mm to 40 mm or 50 mm to 60 mm (i.e., ranging between any two of the preceding numerical values), commonly ranging from 5 to 13 mm or from 15 to 30 mm. In certain beneficial embodiments, the as-manufactured (or unconstrained) length may range from 5 mm or less to 30 mm or more, for example, ranging from 5 mm to 10 mm to 15 mm to 20 mm to 25 mm or 30 mm (i.e., ranging between any two of the preceding numerical values), commonly ranging from 10 mm to 20 mm.

[0487] In certain beneficial embodiments, scaffold mass may range from 1 to 20 mg/mm of length.

[0488] Unless indicated otherwise, scaffold diameters and scaffold lengths given herein refer to unconstrained (manufactured) diameters and lengths.

[0489] The many scaffold embodiments of the present disclosure are self-expanding in that they are manufactured at a first diameter, subsequently reduced or “crimped” to a second, reduced diameter for placement within a delivery catheter, and self-expand towards the first diameter when extruded from the delivery catheter at an implantation site. The first diameter may be at least 10% larger than the diameter of the bodily lumen into which it is implanted in some embodiments. The scaffold may be designed to recover at least about 70%, at least about 80%, at least about 90%, up to about 100% of its manufactured, first diameter, in some embodiments.

[0490] Scaffolds in accordance with the present disclosure are provided with expansion and mechanical properties suitable to render the scaffolds effective for its intended purpose. Two measures of such mechanical properties that are used herein are “radial resistive force” (“RRF”) and “chronic outward force” (“COF”). RRF is the force that the scaffold applies in reaction to a crimping force, and COF is the force that the scaffold applies against a static abutting surface. In certain embodiments, the scaffolds are configured to have a relatively high RRF to be able to hold open bodily lumens, cavities, and nasal features, and the like, yet have a relatively low COF so as to avoid applying possibly injurious forces against the walls of bodily lumens, optic nerve, brain, or the like. For example, the scaffolds of the present disclosure preferably expand to from 70 to 100% of their as-manufactured configuration after being crimped, have an RRF ranging from 50 to 300 mmHg, and/or have an acute COF (at the time of delivery) ranging from to 100 mmHg.

[0491] Scaffolds in accordance with the present disclosure may be formed from a variety of polymeric and non-polymeric materials. Scaffolds in accordance with the present disclosure may be biodegradable or non-biodegradable, or be a combination of both biodegradable and non-biodegradable materials. Where biodegradable, the scaffolds may be fully absorbed, for example, within as little as three weeks or less to as long as 52 weeks or more following placement within a cavity of a patient. In some embodiments, the generally tubular structures may become fully absorbed at some time after 12 weeks of placement and before 32 weeks of placement. Biodegradable devices may also be eliminated though nasal irrigation in other embodiments, as opposed to absorption into nasal mucosa. Devices may also be designed such that discrete portion(s) resorb leading to breakup into predetermined small pieces (typically <10 mm or more typically <5 mm in longest dimension) that can be eliminated from the nasal cavity through normal mucocilliary action, leading to swallowing or expulsion from the nose. In this way, the amount of acidic resorption byproducts (e.g., lactic acid, glycolic acid) which are in contact with the nasal cavity surfaces may be reduced. This can reduce irritation or inflammation of these and surrounding tissues. Additives of a basic nature may also be added to the devices in some embodiments to neutralize the acidic byproducts, which may reduce the inflammatory response associated with the same. Moreover, multiple materials that bioresorb at different rates may also be combined in some embodiments to reduce the amount of material degrading at any one time and hence the biological response.

[0492] In various embodiments, the implantable scaffolds may comprise a generally tubular structure comprising scaffolding material. Scaffolds in accordance with the present disclosure may be fiber-based or non-fiber-based.

[0493] In various embodiments, the scaffolding material may be a biodegradable scaffolding material, typically, a biodegradable scaffolding material that comprises one or more biodegradable polymers. Non-limiting examples of biodegradable polymers for forming the biodegradable scaffolding material include biodegradable polyesters, polycarbonates, polyhydroxyalkanoates, polyanhydrides, and polyorthoesters, non-limiting examples of which include homopolymers of lactic acid (PLA), homopolymers glycolic acid (PGA), homopolymers of trimethylene carbonate (PTMC), homopolymers of caprolactone (PCL), homopolymers of polypropylene fumarate, and homopolymers of dioxanone (PDO), as well as copolymers that comprise two or more of the preceding monomers, for example, poly(lactic acid-co-glycolic acid) (PLGA), poly(lactic acid-co-caprolactone) (PLCL) and poly(glycolic acid-co-caprolactone) (PGCL). Preferred copolymers include PLGA having a molar percentage of lactic acid ranging from 10 to 90% and a molar percentage of glycolic acid ranging from 90 to 10%, more typically lactic acid ranging from 10 to 75% and a molar percentage of glycolic acid ranging from 90 to 25%; for example, PLGA 75:25 (mol/mol) or PLGA (10:90) (mol/mol) may be employed in some embodiments. The composition of PLGA polymers within these ranges may be optimized to meet the mechanical property and degradation requirements of the specific application for which the scaffold is used. In certain embodiments, the biodegradable scaffolding material may comprise a prodrug-based polymer, for example, polyaspirin, which can be used as a single-component or a subcomponent of the generally tubular structure to make scaffolds with degradation-controlled therapeutic-agent-releasing capability.

[0494] In various embodiments, the scaffolding material may be a non-biodegradable scaffolding material, typically a non-biodegradable scaffolding material that comprises one or more non-biodegradable polymers. Non-limiting examples of non-biodegradable polymers for forming the non-biodegradable scaffolding material include polyolefins such as polyethylene (HDPE and LDPE) and polypropylene, halogenated polyolefins such as polyvinyl chloride (PVC) and fluoropolymers including polytetrafluoroethylene (PTFE) and perfluoroalkoxy alkanes (PFAs), polyaromatics such as polystyrene, polyesters such as polyethylene terephthalate (PET), polyamides such as nylon, silicones, mucoadhesive materials and biostable polyurethanes (PU).

[0495] Scaffolds in accordance with the present disclosure may optionally comprise a coating formed of a coating material that at least partially coats the scaffolding material.

[0496] Coatings may be applied for various purposes including mechanical property enhancement, degradation control, and therapeutic agent release and control. Coatings may cover all or a portion of the scaffolds or, in fiber-based techniques, all or a portion of the filaments or strands forming the scaffolds. As used herein “strands” and “filaments” may be used interchangeably and include single fiber strands and filaments (also referred to as monofilaments) and multi-fiber strands and filaments.

[0497] If a scaffold to be coated is a fiber-based structure, coatings may be applied, for example, to individual strands prior to forming the scaffold or applied to the scaffold after the formation thereof. If the scaffold is a non-fiber-based structure, coatings may be applied, for example, to a solid polymer tube or sheet either before or after the removal of material using a suitable cutting technique such as mechanical or thermal cutting. Coatings may be created using any suitable method, including spraying, electrospraying, rolling, dipping, chemical vapor deposition, electrospinning and/or coextrusion, among others. In some embodiments, coatings may include additional agents, such as therapeutic agents, as detailed further below.

[0498] In various embodiments, the coating material may be a biodegradable or nonbiodegradable coating material or a combination of both, typically, a biodegradable coating material that comprises one or more biodegradable polymers or a nonbiodegradable coating material that comprises one or more non-biodegradable polymers. Non-limiting examples of biodegradable polymers for forming the biodegradable coating material include the biodegradable polymers listed above. Non-limiting examples of non-biodegradable polymers for forming the non-biodegradable coating material include the non-biodegradable polymers listed above.

[0499] In various embodiments, coatings are formed that comprise an elastomer. Potential benefits of such coatings include enhancement of mechanical properties. For example, coatings may be made from an elastomeric polymer that, due to its elastic nature when compressed or elongated, applies a force to scaffold that acts in favor of radial expansion, thus enhancing recoverability and/or radial stiffness, among other properties. An additional potential benefit of the elastomer may be to encapsulate the scaffold material (which may be a braid structure, among others), maintaining integrity and providing smooth, soft surfaces that minimize irritation of tissue at contact points while providing good conformability. In this regard, certain aspects of the designs described herein, including those resulting from composite structures and combinations of bioresorbable filaments and elastomeric coatings, provide properties that may not be achieved from other bioresorbable stent designs. Potential benefits include higher radial resistive force and/or chronic outward force with lower amounts of polymer, lower profile (thickness of stent wall) and/or better conformability due to spring-like structures at each fiber crossover point, thereby enabling delivery to the target location through smaller delivery systems or guide catheters and/or providing good apposition and conformability to the target location with smaller as-fabricated stent diameter. Better conformability may lead to more efficient drug delivery to the tissue based as a result of improved tissue contact. Furthermore, better conformability may facilitate manipulation of the implant post-deployment by the surgeon to a desired position. For example, when readjusting one side of the implant, the opposite side of the implant has a tendency to readjust its position unless it is well-contoured and adherent to the tissue.

[0500] Coating thickness for the elastomer coating may vary widely, with typical coating thicknesses ranging, for example, from 5 to 50 μm, among other thicknesses. Where a braided scaffold is coated, the elastomer coating may range, for example, between 30 and 150% by weight of the braided scaffold substrate.

[0501] Elastomers include thermoset and thermoplastic elastomers. The thermoset or thermoplastic elastomer beneficially has a glass transition temperature (Tg) that is lower than room temperature (25° C.) and is more beneficial when lower than 10° C. The thermoset elastomers may provide a high elongation to break with low permanent deformation under cyclic mechanical testing. Examples of elastomers include, for example, poly(glycolide-co-£-caprolactone) (PGCL) or poly(lactide-co-ε-caprolactone) (PLCL), including poly(L-lactide-co-ε-caprolactone) and poly(D,L-lactide-co-ε-caprolactone). In certain embodiments, the PLCL may have a molar percentage of lactide ranging from 20 to 80% and a molar percentage of caprolactone ranging from 80 to 20%, more typically, a molar percentage of lactide ranging from 30 to 50% and a molar percentage of caprolactone ranging from 50 to 70%.

[0502] In certain embodiments, the biodegradable coating material is a thermoset elastomer formed from polymeric polyols including diols, triols, tetraols and/or higher alcohols. Such polymers may be crosslinked with a crosslinker that is a bi- or multifunctional small molecule or polymer. For example, crosslinks may be formed by reacting such polymers with bi- or multi-functional isocyanates, which may be in form of a small molecule or polymer.

[0503] In the event that the coating comprises a thermoset elastomer polymer, the crosslink density may be varied to yield desired mechanical properties. For example, optional chain terminators may be used in thermoset elastomeric materials such as polyester urethanes to control crosslink density. The chemical crosslink density is adjusted by using such chain terminators to control the degree of crosslinking taking place during the polyester-urethane curing. The crosslink density of the resultant elastomers depends on the concentration of chain terminators incorporated into the elastomeric network. Examples of suitable chain terminators include any suitable monofunctional compound such as monofunctional isocyanates, alcohols, amines, acyl chlorides, and sulfonyl chlorides.

[0504] In certain embodiments, the thermoset elastomer comprises a polyester polyol, diisocyanate crosslinker and an optional chain terminator. Such a thermoset elastomer may be prepared by a process that comprises the steps of: at least partially dissolving a polyester polyol in a solvent to form a solution; adding a diisocyanate crosslinker to said solution; optionally adding a chain terminator to said solution; coating said solution onto the scaffolding material; and curing said solution. Where solvent-based processing is employed, a less volatile co-solvent may be used to improve the node accumulation of thermoplastic elastomers during the coating process.

[0505] Non-limiting examples of suitable polyols for forming urethane-crosslinked elastomers include, for example, branched (3 arms or more) poly(lactic acid-co-caprolactone) (PLCL) and poly(glycolide-co-caprolactone) (PGCL) polyols. Besides branched polymers, linear polymer diols may also be used to create an elastic coating upon curing with isocyanates (e.g., hexamethylene diisocyanate) and other appropriate reagents. To reduce inflammation caused by material degradation, poly(trimethylene carbonate) (PTMC) based polyols may also be used to create an elastic coating. Various catalysts, including but not limited to, Sn(Oct).sub.2, Zn(Oct).sub.2, dibutyl tin dilaurate (DBTL), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicycloundec-7-ene (DBU), may be used to facilitate the curing process.

[0506] In some embodiments, scaffolds and/or coatings may be fabricated using a shape-memory polymer that can change in size, shape, and/or conformability to mold to the desired anatomy. Non-limiting examples of shape-memory polymers include segmented polyurethanes made of oligolactide, oligocaprolactone, oligolactide-co-glycolide, oligo(trimethylene carbonate), or oligodioxanone coupled isocyanates and various chain extenders, (multi)block copolymers of lactide (glycolide) and caprolactone, dioxanone, or trimethylene carbonate, polymer blends of polylactide and polyamide elastomers.

[0507] As previously indicated, scaffolds in accordance with the present disclosure may be fiber-based or non-fiber-based. In fiber-based embodiments, polymeric materials may be first manufactured into fibers with cross-sectional dimension ranging, for example, from 10 μm to 1000 μm, more typically, 100 μm to 300 μm. Such fibers may be formed using a number of technologies including, for example, extrusion or spinning technologies.

[0508] The shape of the cross-section of the fibers may vary widely. Referring to FIG. 1A, such cross-sections include fibers having round cross-section 10, oval cross-section 12, and polygonal cross-section (e.g., triangular cross-section 14, quadrilateral cross-section 16, for instance, in the shape of a rectangle, parallelogram, trapezoid, etc., pentagonal cross-section, hexagonal cross-section 18, and so forth). Fiber cross-section may be varied by selecting a die of suitable cross-section for use during fiber manufacture.

[0509] Polymeric materials may also be formed into sheets, for example, through a suitable casting or extrusion process (e.g., solvent casting, melt casting, solvent-based extrusion, melt extrusion, etc.) The sheets may thereafter be cut into fibers (e.g., fibers having a polygonal cross-section, for instance, in the shape of a triangle or a quadrilateral such as rectangle, parallelogram, trapezoid, etc.).

[0510] The strength of the fibers may be optimized in certain embodiments, for example, by drawing at appropriate draw ratios or annealing at appropriate temperatures.

[0511] Strength and/or flexibility of the fibers may also be optimized by braiding fibers of homogeneous or heterogeneous cross-section into multi-fiber strands (e.g., fish-wire type structures). The fibers that are braided may be of the same composition or of different composition. Moreover, the fibers that are braided may be of the same diameter or different diameter. Two embodiments are shown in FIG. 1B, which illustrates (a) a cross-section of a multi-fiber strand 11 formed from strands of the same material and having the same diameter and (b) a cross-section of a multi-fiber strand 13 formed from strands of different composition and having different diameter.

[0512] Once the polymeric strands are prepared, fiber-based scaffolds may be made thereof. For example, single-fiber strands and/or multi-fiber strands of various shapes (e.g., as illustrated in FIGS. 1A-1B, among others) may be braided into a generally tubular structure. The strands that form the braids may vary widely in diameter, ranging, for example, from 10 to 1000 μm, among other possibilities. In certain embodiments, the materials forming the strands may have an elastic modulus within the range of about 1 GPa to about 10 GPa, and more preferably within the range of about 4-9 GPa.

[0513] To facilitate low-profile aspects of the present disclosure (e.g., the delivery of the scaffolds into small diameter cavities), in certain beneficial embodiments, the strands used in forming scaffolds may have a diameter ranging from 100 to 500 μm, more beneficially ranging from 125 to 250 μm. The use of small diameter strands results in a scaffold with minimal wall thickness and the ability to collapse (i.e., to be crimped) within low diameter catheter delivery systems. In certain embodiments, the diameters of strands may be chosen so as to render the scaffold deliverable from a 15 French delivery catheter or smaller, from a 9 French delivery catheter or smaller, from a 6 French delivery catheter or smaller, or even from a 4 French delivery catheter or smaller.

[0514] FIG. 2 illustrates an embodiment of a braided scaffold 100, which comprises at least one strand (e.g., a single-fiber or multi-fiber strand) woven to form a substantially tubular configuration having a length 130, a width 131, and first and second ends 132, 133 along the longitudinal dimension. For example, the tubular structure may comprise two sets of strands 110 and 120, with each set extending in an opposed helical configuration along the longitudinal dimension of the scaffold. In certain embodiments, the number of helical strands forming the scaffold may range, for example, from 8 to 48 strands, among other possibilities. The sets of strands 110 and 120 cross each other at a braid angle 140. The braid angle 140 may range, for example, from about 30 degrees or less to about 150 degrees or more, among other values, for example, ranging anywhere from 30 degrees to 40 degrees to 50 degrees to 60 degrees to 70 degrees to 80 degrees to 90 degrees to 100 degrees to 110 degrees to 120 degrees to 130 degrees to 140 degrees to 150 degrees (i.e., ranging between any two of the preceding numerical values). Strands may be woven together using a variety of methods known in the art including, for example, various 1×1, 1×2 and 2×2 designs and may be woven using particular known weave patterns such as Regular pattern “1 wire, 2-over/2-under”, Diamond half load pattern “1 wire, 1-over/1-under”, or Diamond pattern “2 wire, 1-over/1-under”.

[0515] Various factors contribute to the radial strength of scaffold 100, including the diameter(s) of the strands, the braid angle 140, the strand material(s), and the number of strands used, among others.

[0516] Strands may cross each other at a braid angle which is constant or which may change around the circumference of the scaffold and/or along the longitudinal dimension of the scaffold. FIG. 3A shows an embodiment in which a scaffold 100 has strands of constant braid angle, whereas FIG. 3B shows an embodiment in which a scaffold 100 has strands of variable braid angle. In the particular embodiment of FIG. 3B, a first region 100a having strands of a first braid angle transitions into a second region 100b having strands of a second braid angle that is less than the first braid angle. Various filament braiding patterns may be used to manufacture such constructs.

[0517] Potential attributes of a design with variable braid angles include one or more of the following, among others: (1) it allows for the orientation of segments with specific density for preferential therapeutic agent delivery; (2) it allows for tailored radial force depending on scaffold location; and (3) it may be used to provide a tapered tubular design that is useful for non-cylindrical anatomy.

[0518] In general, the shape and diameter of a scaffold in accordance with the present disclosure may change along the length of the device. In certain embodiments, in a cylindrical design the diameter at the ends of the device may be larger than the diameter at the midpoint (e.g. a dumbbell or hourglass shape). For instance, the diameter at the ends of the device may be 1.5 times or more, even 2 times or more, than the diameter at the midpoint. As another example, the shape of the device may be triangular at one end and hexagonal at the other end.

[0519] Radial stiffness for braided scaffolds may be tailored by partially or completely locking various strand cross-over points (also referred to as “nodes”). Nodes may be partially or completely locked, for example, by welding the strands at cross-over points, for instance, using heat (e.g., using a suitable laser such as a pico or femto laser), by using a suitable adhesive, by wrapping crossover points with a suitable filament, or by coating cross-over points with a suitable material that holds the filaments together, among other possible techniques. In some embodiments, elastomers may be coated onto the braids, for example, using procedures such as those described in U.S. Pat. Nos. 8,137,396, 8,540,765, and 8,992,601, the disclosures of which are hereby incorporated by reference.

[0520] Underlying braids, either with or without previously locked nodes, may be subject to elastomer coating. One embodiment is illustrated in FIG. 4, which shows a braided scaffold 100 that is completely coated with an elastomer 100e. Varying the node accumulation of the coated elastomer may optimize both radial resistive force (RRF) and chronic outward force (COF).

[0521] In alternative embodiments, scaffolds may be provided in which the nodes of the braided structure are connected using an elastic member such as an elastic filament or strand. One such embodiment is illustrated in FIG. 5, which shows a scaffold 100 in which an elastic strand 111 is attached to the braid 110 at various points along the length of the braid 110. In these embodiments, the braid itself provides the framework to support placement, while the elastic filament or strand 111 is provided to enhance scaffold recovery during deployment. The elastic filament or strand 111 may be, for example, woven into the scaffold 100 during braiding process or introduced to the scaffold 100 after it is formed. In the latter case, the braid 110 forming the scaffold 100 may be made from softer, non-elastic materials that conform to anatomical walls and have desired degradation profiles. The number of elastic filaments or strands 111 used in a given scaffold 100 may be tailored to afford appropriate recovery and radial stiffness.

[0522] A conformable scaffold is desirable in various embodiments, as it may be used to improve apposition to contacted tissues, reduce damage to the contacted tissue and, where a therapeutic agent is delivered, also increase the therapeutic agent delivery efficacy due to increased tissue contact.

[0523] Various strategies may be employed to increase conformability of the braided scaffolds. For example, in some embodiments, some or all of the nodes of the braids may be partially locked or not locked at all to allow at least some filaments at least some freedom to slide over one another. In a constrained space, scaffolds with freely movable filaments will have a tendency to better adapt to the geometry of the surrounding environment.

[0524] Alternatively or in addition, scaffolds may be braided from filaments of different stiffness (e.g., having a combination of higher and lower stiffness). The stiffness of a given strand is determined, for example, by its inherent material properties, by its processing conditions, and by its dimension. One embodiment of this type of scaffold is schematically illustrated in FIG. 6A in which a scaffold 100 is shown that is formed from strands of higher stiffness 112 and strands of lower stiffness 113. In one specific embodiment, the strands of higher stiffness 112 may have an elastic modulus higher than 3 GPa and filament diameter greater than 100 μm, while the strands of lower stiffness 113 may have an elastic modulus lower than 3 GPa and filament diameter less than 200 μm. Filaments with lower stiffness may provide a weaker point in the scaffold to allow for deformation to comply with the anatomy, whereas filaments with higher stiffness may maintain mechanical integrity.

[0525] Conformability may also be improved by removing some of the strands from within the braided structure. One embodiment of this type of scaffold is schematically illustrated in FIG. 6B in which a scaffold 100 is shown in which cells of varying size are formed. In particular, a scaffold containing larger diamond shaped cells 114 and smaller diamond shaped cells 115 are shown. In some embodiments, a severed strand may be partially or completely locked at a cross-over point nearest to the severed tip of the strand.

[0526] In related embodiments, different sized cells are created during the course of the braiding process, for example, through selection of a suitable braiding pattern. One embodiment of a scaffold 100 having larger braided cells 114 and smaller braided cells 115 is shown in FIG. 7.

[0527] Where cells of differing sizes are formed, the larger cells may have an area ranging from 1.1 times to 10 or more times an area of the smaller cells.

[0528] Potential advantages of scaffolds having a combination of larger and smaller cells is that the larger cells may provide flexibility (e.g. for ease of crimping and better conformability), whereas the smaller cells may maintain mechanical integrity.

[0529] Another route to create conformable scaffolds is to braid the scaffolds using a rigid rubber material such as carbon fiber reinforced silicone, poly(acrylonitrile butadiene), and poly(styrene butadiene) rubbers, among others. This results in completely elastic braids.

[0530] In some embodiments, a coating layer may be formed over all or a part of the scaffold structure. By employing a relatively non-elastic material for the coating layer (e.g., one formed using a relatively stiff polymer such as D,L-PLGA), the stiffness of the scaffold may be improved. Moreover, where the implant is formed using braids that are inherently elastic and where the coating layer is a degradable layer, upon degradation of the degradable layer, the scaffold strands will have increased conformability.

[0531] Furthermore, the coating layer may be applied in a pattern in order to tailor the conformability of the braided scaffolds. As one specific example, FIG. 6C shows an embodiment of a scaffold 100 where coated regions 116 are provided at each end of the scaffold 100 while an uncoated region 117 is provided at the center of the scaffold 100. Such a design may be used to provide ends having enhanced stiffness, which may allow the device to be better anchored into the desired location. Moreover, leaving the middle region of the scaffold 100 uncoated may enhance the ability of the stent to comply with the shape of the desired location at the time of implantation. As another specific example, FIG. 6D shows an embodiment of a scaffold 100 where coated regions 116 and uncoated regions 117 are provided in an alternating pattern. The presence of uncoated regions 117 provides regions of increased flexibility along the length of the scaffold, which may provide enhanced conformability to irregular surfaces such as those associated with the anatomy of the desired placement location.

[0532] Regions of coated and uncoated material may be provided using various techniques. For instance, in some embodiments, a mask may be used in a spray coating process to create specific patterns of coated and uncoated regions.

[0533] By masking a part of the tubular braids longitudinally during spray coating, a U-shaped coating region (when viewed longitudinally) may be created. In these scaffolds, the coated region is relatively stiff while the uncoated region is relatively soft. The coated region would provide scaffold recoverability after deployment. On the other hand, the soft uncoated region may readily deform to adapt the irregular surface of the desired location, affording optimized conformability. In one particular embodiment, such a scaffold may be useful to maintain patency in select cases where an opening is made between the left and right paranasal sinuses.

[0534] In some embodiments, the scaffold may be cut longitudinally, allowing the circumference of the scaffold to be readily resized to match the geometry of the anatomy upon deployment, which may provide better compliance and conformability.

[0535] To reduce potential tissue irritation or patient discomfort caused by sharp scaffold edges, the scaffold edges may be coated and/or braided scaffolds may be made in which the end filaments are turned back toward the center of the scaffold. For instance, the filament ends may be woven back into the scaffold structure and bonded, for example, at the nodes. Bonding may be conducted using the techniques described hereinabove for bonding filaments at the nodes (e.g., by welding, application of a suitable adhesive, application of an elastomeric coating, etc.). A scaffold 100 of this type is schematically illustrated in FIG. 8 in which the end filaments 118 are turned back toward the center of the scaffold 100.

[0536] To the extent that difficulty may be encountered when short scaffolds are braided on large diameter mandrels (i.e., when forming scaffolds with large diameter to length ratios), zig-zag strands, including single- and multi-fiber strands, may be fabricated prior to braiding. The zig-zag strands may then be wound or looped around the mandrels, preferably in braided pattern. The ends of the filaments may then be attached, for example, using the techniques described hereinabove for bonding filaments at the nodes (e.g., by welding, application of a suitable adhesive, application of an elastomeric coating, etc.) to complete the braided structure. The size and shape of the final scaffold may be controlled by the turn angle, orientation and strut length of the zig-zag filaments. Such a braid may also have fold-back ends as depicted above.

[0537] In certain embodiments, it is beneficial to provide scaffolds with a capability of being readily removed if it is desired to do so. In the case of a relatively soft braided scaffold, a tool with one or more hooks at the end may be used to capture a distal end of the implanted scaffold. Alternatively, the device could be removed by standard surgical instruments available to ENT surgeons. Then, the braid may be inverted by pulling the end, and thus the exterior surface, into the lumen. In this way, the scaffold may be removed by peeling off the sinus wall, reducing additional abrasion, irritation, and damage to sinus tissue.

[0538] Other scaffolds are based on non-braided structures or hybrid braided/non-braided structures.

[0539] For instance, in various embodiments, scaffolds are provided which are formed from woven or knitted strands. A scaffold 100 in the form of a knitted tube is illustrated in FIG. 9. Such a woven or knitted scaffold may provide the mechanical properties necessary to provide a stenting function, while also having enhanced compliance and conformability (as well as facilitating therapeutic agent delivery in some embodiments). In addition, in the case of a knitted structure, one end of a single strand used to form the tube may be pulled to unravel the stent, enabling removal of the scaffold, in some embodiments.

[0540] In various other embodiments, scaffolds may be in a spiral (e.g., helical) form. In some of these embodiments, a spiral form may be formed from a single strand (e.g., a single- or multi-fiber strand). An example of such a scaffold 100 is schematically illustrated in FIG. 10.

[0541] In other of these embodiments, a spiral form may be formed from multi-stranded constructs. Examples of multi-stranded constructs include, for example, substantially two-dimensional structures (e.g., ribbon-shaped structures) which can be shaped into a spiral form. Two embodiments of spiral-shaped scaffolds of this type are shown in FIG. 11A and FIG. 11B. In the embodiment shown in FIG. 11A, a spiral shaped scaffold 100 is formed from a pre-existing tubular structure such as, for example, braided tubular structure (e.g., one of those previously described), which is subsequently cut into a spiral. In the embodiment shown in FIG. 11B, a scaffold 100 is formed by fashioning a previously formed substantially two-dimensional braid pattern 119 into a spiral structure, for example, by placing the substantially two-dimensional braid pattern on a mandrel and annealing it for a time and at a temperature suitable to form the two-dimensional braid pattern into a spiral shape. Examples of such braid patterns include multi-carrier braid patterns, such as a 2-carrier (shown in FIG. 11B), 3-carrier, 4-carrier, etc. braid pattern.

[0542] It is noted that scaffolds analogous to the various braided structures described herein may be in the form of a unitary polymeric structure. The use of a unitary polymeric structure may provide a reduced profile when compared to the use of fiber-based techniques, which yield a minimum profile that is the sum of the widths of overlapping strands. One embodiment of such a structure is shown in FIG. 15, in which a scaffold 100 is illustrated and is characterized by a regular, repeating pattern such as a lattice structure. When the scaffold 100 is a unitary polymeric structure, it may be fabricated using a variety of suitable techniques, such as by mechanical cutting or laser cutting a pattern into a solid polymer tube or a solid polymer ribbon

[0543] In various other embodiments, the scaffold may be in the form of an open cylinder. For example, as shown in FIGS. 12A and 12B, the scaffold 100 may be formed form a series of individual hoops 121 which are axially aligned with one another and connected at one end. In the embodiment shown in FIG. 12A, individual hoops 121 are solid hoops (e.g., in the form of a ribbon). In the embodiment shown in FIG. 12B, individual hoops 121 comprise cells, in particular, diamond-shaped cells analogous to those formed with a 2-carrier braid. Benefits of these designs may include one or more of the following, among others: the hoops are straightforward to crimp to size; and upon delivery, the scaffold unfurls to an expanded diameter. Because each hoop is allowed to expand to different widths, the scaffold may be more conformal in variable sized spaces.

[0544] In still other embodiments, a scaffold 100 may be in the form of a polymeric tube such as that shown in FIG. 13. Such a device is beneficial, for example, in that it may conform to the wall 200 of the desired location and, optionally release one or more therapeutic agents. The tube may utilize materials such as the scaffold materials described above, among others, and include thermally-forged PCL, or PLCL with high caprolactone content, among many other possible materials.

[0545] In a related device design, a tubular conformal scaffold like that shown in FIG. 13 may be attached to a crimpable three-dimensional support structure which may assist the tubular scaffold in expansion and support. A specific example of such a device is shown in FIG. 14, which shows the tubular scaffold 110 attached to a crimpable three-dimensional structure 122. The structure 122 is crimpable to allow for minimally invasive delivery. Structures 122 may be provided at the ends of the tubular scaffold 110, and if desired, at one or more points along a length of the tubular scaffold 110. Examples of materials suitable for forming the crimpable three-dimensional structure include degradable or non-degradable elastomeric materials that can be compressed and recover from that deformation. In other embodiments, braided stent structures like those discussed hereinabove may be used as crimpable three-dimensional structures.

[0546] Supplemental agents such as therapeutic agents and inactive release-controlling agents may be integrated into the various devices described herein.

[0547] Examples of therapeutic agents are any suitable agents having desired biological effects, including small molecule agents, biologies, cells, including stem cells, gene therapies and RNAi, among others. Specific examples of therapeutic agents include: analgesic agents including simple analgesics such as aspirin and paracetamol, nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, naproxen, celecoxib, ketoprofen, piroxicam and sulindac, and opioids such as codeine tramadol, dextropropoxyphe, paracetamol, morphine, oxycodone and pethidine hydrochloride; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; statins such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; steroidal anti-inflammatory drugs such as glucocorticoids, mometasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, dexamethesone, cortisone, prednisone, methylprednisolone, triamcinolone acetonide, betamethasone, dexamethasone, prednisolone, corticosterone, estrogen, sulfasalazine, rosiglitazone, mycophenolic acid, and mesalamine; antihistamines including Hi-receptor antagonists such as diphenhydramine, loratadine, fexofenadine, cyproheptadine, promethazine, desloratadine, chlorpheniramine, hydroxyzine and pyrilamine and hh-receptor antagonists such as cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine and tiotidine; antimicrobial agents such as mupirocin, gentamycin and tobramycin; antibiotic agents such as penicillin, cefoxitin, oxacillin and tobramycin; endostatin, angiostatin and thymidine kinase inhibitors, and its analogs or derivatives; antileukotriene agents (e.g. monteleukast, zafirlukast, zileuton, etc.); antifungal agents; and probiotics, among many others.

[0548] Further examples of therapeutic agents may be selected from anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone), enoxaparin, hirudin; antiproliferative agents such as angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, acetylsalicylic acid, paclitaxel, sirolimus, tacrolimus, everolimus, zotarolimus, vincristine, sprycel, amlodipine and doxazosin; immunosuppressants such as sirolimus, tacrolimus, everolimus, zotarolimus, and dexamethasone; antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, cladribine, vincristine, epothilones, methotrexate, azathioprine, halofuginone, adriamycin, actinomycin and mutamycin; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin (aspirin is also classified as an analgesic, antipyretic and anti-inflammatory drug), dipyridamole, hirudin, prostaglandin inhibitors, platelet inhibitors and antiplatelet agents such as trapidil or liprostin, tick antiplatelet peptides; DNA demethylating drugs such as 5-azacytidine, which is also categorized as a RNA or DNA metabolite that inhibit cell growth and induce apoptosis in certain cancer cells; vascular cell growth promotors such as growth factors, Vascular Endothelial Growth Factors (VEGF, all types including VEGF-2), growth factor receptors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as antiproliferative agents, growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; and agents which interfere with endogenous vasoactive mechanisms; anti-oxidants, such as probucol; angiogenic substances, such as acidic and basic fibrobrast growth factors, estrogen including estradiol (E2), estriol (E3) and 17-Beta Estradiol; drugs for heart failure, such as digoxin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors including captopril and enalopril, statins and related compounds; macrolides such as sirolimus and everolimus; and agents that have a primary mechanism of action of inhibiting extracellular matrix remodeling, and a secondary mechanism of action of inhibiting cell proliferation such as 5-fluorouracil, doxycyclin, carvedilol, curcumin, and tranilast.

[0549] Other therapeutic agents include bacteria or other microflora that may be beneficial to re-establishing a healthy microbiome in the nasal cavity and sinuses as well as agents or nutrients that may promote a healthy microbiome.

[0550] Inactive release-controlling agents may also be included to enhance control over the therapeutic agent release kinetics. Examples of inactive release-controlling agents include soluble polymers such as polyethylene glycol (PEG) (also known as polyethylene oxide, PEO), PEG-vinyl alcohol copolymers, polyacrylate and polymethacrylate esters containing cationic and anionic functionality, polyvinyl pyrrolidone, and dextran, as well as small molecule additives such as cyclodextrin or citrate esters such as acetyltributyl citrate (ATBC) or acetyltriethyl citrate (ATEC).

[0551] In embodiments where the scaffold delivers one or more therapeutic agents at the site of implantation, the therapeutic agent(s) may be provided in the device for delivery therefrom in a number of ways.

[0552] For example, the therapeutic agent may be directly embedded within a polymeric construct (e.g., filaments, sheets, solid tubes, etc.) that is subsequently used to form a generally tubular scaffold as described herein. In one embodiment, therapeutic agent and polymer(s) are dissolved in an appropriate solvent to make a homogenous solution or a suspension, or therapeutic agent and polymer(s) are heated to form a polymer melt containing the therapeutic agent. The solution, suspension or melt is then subjected to suitable solvent-based or melt-based processing such as extrusion, wet spinning, dry spinning, melt spinning, electrospinning or other process to afford therapeutic-agent-loaded polymeric constructs (e.g., filaments, sheets, tubes, etc.) with embedded therapeutic agents. In some embodiments, a polymeric region that does not contain a therapeutic agent (e.g., a polymer core) is coextruded with a therapeutic-agent-loaded polymeric coating to form therapeutic-agent-loaded polymeric constructs.

[0553] In some embodiments, therapeutic-agent-loaded polymeric constructs may then be subsequently processed into additional forms that are subsequently used to form generally tubular scaffolds as described herein. As a specific example, a solvent-cast therapeutic-agent-loaded polymeric construct in the form of a sheet may be made by controlled evaporation of a solution of a therapeutic agent and one or more carrier polymers. After removal of the solvent(s), the therapeutic-agent-loaded polymer sheet may be laser cut into therapeutic-agent-loaded polymeric constructs in the form of flat filaments for braid manufacture.

[0554] In some embodiments, the therapeutic agent may be applied onto a pre-formed construct (e.g., a filament, a sheet, or a tube, including a pre-formed device scaffold) in the presence or absence of a carrier material (e.g., a polymeric coating material such as those described above) using a suitable application technique such as spray-coating, dip-coating, rolling or vapor deposition, among others. The therapeutic agent releasing profile may be tailored, for example, by the thickness of the coating layer, by the addition of inactive ingredients and, where a polymer is provided as a carrier, changing the carrier polymer (e.g. changing the composition and/or molecular weight of the polymer) and/or the therapeutic-agent-to-polymer ratio.

[0555] A topcoat of a therapeutic-agent-free polymer layer may also be employed to regulate the delivery of the therapeutic agent from the device into bodily tissue. In embodiments pertaining non-biodegradable topcoats, the topcoat may act as a diffusion barrier such that the rate of delivery of the therapeutic agent(s) is limited by the rate of its diffusion through the topcoat. In some embodiments pertaining to biodegradable topcoats, the topcoat may also act as a diffusion barrier such that the rate of delivery of the therapeutic agent(s) is limited by the rate of its diffusion through the topcoat. In other embodiments pertaining to biodegradable topcoats, the therapeutic agent(s) cannot diffuse through the topcoat, such that delivery thereof is simply delayed until the degradation of the topcoat is complete.

[0556] Electrospinning provides another potential method to introduce therapeutic agent onto a pre-formed construct. In one embodiment, a fiber-based or non-fiber-based scaffold may be covered by an electrospun fiber mesh, such as a core-sheath fiber mesh. During electrospinning, the therapeutic agent may be either dissolved or suspended in a core polymer solution. The therapeutic agent release profiles may be tuned by adjusting the therapeutic agent loading, the particulate size of the therapeutic agent (where a suspension is employed), the types of polymers used to form the core and sheath, respectively, as well as the thickness of the sheath.

[0557] In other embodiments, core-sheath fibers are first fabricated through coaxial electrospinning of a core polymer solution or suspension with therapeutic agent and a sheath polymer solution. The therapeutic-agent-loaded fibers may be further braided onto a multi-fiber strand that will be used to manufacture devices. For example, a fish-wire-shaped composite strand may be formed and thereafter fabricated into a braided scaffold as described previously. In these designs, the therapeutic agent release may be dictated by the electrospun fibers.

[0558] In some embodiments, biologically active agents such as proteins and/or polysaccharides may be incorporated into electrospun fibers. In some embodiments, the devices described herein can be used in conjunction with sinuplasty. For example, scaffolds such as those described herein can be deployed with the assistance of an expandable device such as an expandable frame (e.g., an expandable wire frame) or a balloon, among other possibilities. In such embodiments, a scaffold in accordance with the present disclosure may be positioned on, in, under, proximal to, or distal to the expandable device, either at a manufacturing site or by a healthcare professional at the time of delivery. The expandable device may be a drug-eluting device (e.g., via a drug-containing coating disposed on the expandable device) or a non-drug-eluting device. Examples of therapeutic agents which may be released by a drug-eluting device are described above.

[0559] Thus, in the case of a balloon, the balloon may be coated or uncoated, and a scaffold in accordance with the present disclosure may be positioned on, in, under, proximal to, or distal to a balloon catheter suitable for sinuplasty, either at a manufacturing site or by a healthcare professional at the time of delivery. The catheter may include an inflatable balloon assembly disposed at or near a distal end of a catheter shaft that comprises an inflation lumen for the balloon. In an uninflated state, the balloon assembly does not significantly increase the overall width of the distal end of the catheter. This allows the distal portion of the catheter to be inserted into a patient and guided to a desired treatment site in the patient. Once at the treatment site, the balloon assembly is inflated to position the scaffold against the sinus wall proximate to the treatment site. The balloon assembly can include any number of individual balloons in a number of configurations, depending upon the treatment site. Additionally, the sinuplasty may be completed before delivery of the scaffold, after delivery of the scaffold, simultaneously with delivery of the scaffold, or any combination of perioperative procedural sequences.

In some embodiments, the devices described herein can be used as an adjunctive therapy. For instance, scaffolds such as those described herein can be deployed into the sinus cavities using a therapeutic-agent-eluting delivery device such as, for example, a therapeutic-agent-eluting balloon. Alternatively, scaffolds can be deployed into the sinus cavities, after the cavities have been treated with a therapeutic-agent-releasing spray such as a hydrogel spray, or irrigation liquid that contains one of the therapeutic agents previously described in this disclosure.

[0560] The scaffolds of the present disclosure may be radiopaque such that they are visible using conventional fluoroscopic techniques. In one embodiment, radiopaque additives are included within the polymer material of the scaffold and/or its coating, where present. Examples of suitable radiopaque additives include particles comprising iodine, bromine, barium sulfate, platinum, iridium, tantalum, and/or palladium. In another embodiment, the radiopaque groups, such as iodine, are introduced onto the polymer backbone. In yet another embodiment, one or more biostable or biodegradable radiopaque markers, for example, comprising platinum, iridium, tantalum, and/or palladium may be produced in the form of a tube, coil, wire, sphere, or disk, which is then placed at the ends of the scaffold or at other predetermined locations thereon.

[0561] To facilitate delivery, the scaffold may be loaded into a delivery catheter just prior to being implanted into a patient. Loading the scaffold in close temporal proximity to implantation avoids the possibility that the polymer of the scaffold will relax during shipping, storage, and the like within the delivery catheter. One aspect of the disclosure thus includes a method of delivering a scaffold of the disclosure that comprises a step of loading the scaffold into a delivery catheter within a short period of time, for example, within one hour, before implantation into a body lumen. It should be noted, however, that it is not required that the scaffolds of the present disclosure are loaded into delivery catheters just prior to being implanted.

[0562] In certain embodiments, scaffolds may be provided which are suitable for implantation into the vacated space that is formed during an ethmoidectomy, among other uses (e.g., using a 6 mm catheter, among other devices). Such scaffolds may range, for instance, from 10 to 30 mm in diameter, more particularly, from 15 to 20 mm in diameter, among other possible values. Such scaffolds may range, for instance, from 5 to 20 mm in length, more particularly, from 8 to 12 mm in length, among other possible values. In certain beneficial embodiments, the scaffolds comprises a braided scaffold material, which may comprise, for example, from 8 to 64 braiding strands, more particularly, from 16 to 32 braiding strands, among other possible values. In certain beneficial embodiments, braid angle may vary, for instance, from 30 to 150 degrees, more particularly, from 60 to 130 degrees, among other possible values. In certain beneficial embodiments, diameter of the strands that form the braids may vary from 50 to 500 μm, more particularly, from 150 to 300 μm, among other possible values. In certain beneficial embodiments, scaffold mass may range, for instance, from 1 to 20 mg/mm of length, more particularly, from 2 to 10 mg/mm, among other possible values. In certain beneficial embodiments, scaffolds have a % diameter recovery of at least 85% after being compressed to a diameter of that is 30% of the unconstrained diameter for 10 minutes. Where drug is released, in non-refractory patients the drug may be released over a period of 3 to 6 weeks, among other values, whereas in refractory patients the drug may be released over a period of 8 to 26 weeks, among other values.

[0563] In certain embodiments, scaffolds may be provided which are suitable for implantation into the middle meatus space, among other uses (e.g., using a 3-4 mm delivery catheter, among other possible devices). Such scaffolds may range, for instance, from 5 to 20 mm in diameter, more particularly, from 10 to 15 mm in diameter, among other possible values. Such scaffolds may range, for instance, from 5 to 20 mm in length, more particularly, from 8 to 12 mm in length, among other possible values. In certain beneficial embodiments, the scaffolds comprises a braided scaffold material, which may comprise, for example, from 8 to 64 braiding strands, more particularly, from 16 to 32 braiding strands, among other possible values. In certain beneficial embodiments, braid angle may vary, for instance, from 30 to 150 degrees, more particularly, from 60 to 130 degrees, among other possible values. In certain beneficial embodiments, diameter of the strands that form the braids may vary from 100 to 500 μm, more particularly, from 150 to 300 μm, among other possible values. In certain beneficial embodiments, scaffold mass may range, for instance, from 1 to 20 mg/mm of length, more particularly, from 2 to 10 mg/mm of length, among other possible values. In certain beneficial embodiments, scaffolds have a % diameter recovery of at least 85% after being compressed to a diameter of that is 30% of the unconstrained diameter for 10 minutes. In certain beneficial embodiments, scaffolds have a RRF ranging from 30 to 500 mmHg upon being measured in an MSI radial force tester at a diameter less than the manufactured diameter, among other possible values. In certain beneficial embodiments, scaffolds have an acute COF ranging from 5 to 100 mmHg upon being measured in an MSI radial force tester at a diameter less than the manufactured diameter, among other possible values. Where drug is released, it may be released over a period of 8 to 26 weeks, among other values.

[0564] In certain embodiments, scaffolds may be provided which are suitable for implantation (e.g., using a 3-4 mm delivery catheter, among other possible devices). Such scaffolds may range, for instance, from 4 to 20 mm in diameter, more particularly, from 6 to 10 mm in diameter, among other possible values. Such scaffolds may range, for instance, from 5 to 20 mm in length, more particularly, from 6 to 12 mm in length, among other possible values. In certain beneficial embodiments, the scaffolds comprise a braided scaffold material, which may comprise, for example, from 8 to 64 braiding strands, more particularly, from 16 to 32 braiding strands, among other possible values. In certain beneficial embodiments, braid angle may vary, for instance, from 30 to 150 degrees, more particularly, from 60 to 130 degrees, among other possible values. In certain beneficial embodiments, diameter of the strands that form the braids may vary from 100 to 500 μm, more particularly, from 150 to 300 μm, among other possible values. In certain beneficial embodiments, scaffold mass may range, for instance, from 1 to 20 mg/mm of length, more particularly, from 2 to 10 mg/mm, among other possible values. In certain beneficial embodiments, scaffolds have a % diameter recovery of at least 85% after being compressed to a diameter of that is 30% of the unconstrained diameter for 10 minutes. In certain beneficial embodiments, scaffolds have a RRF ranging from 30 to 500 mmHg upon being measured in an MSI radial force tester at a diameter less than the manufactured diameter, among other possible values. In certain beneficial embodiments, scaffolds have an acute COF ranging from 5 to 100 mmHg upon being measured in an MSI radial force tester at a diameter less than the manufactured diameter, among other possible values. Where drug is released, it may be released over a period of 6 to 26 weeks, among other values.

[0565] Drug Release Kinetics.

[0566] As drug is released from a scaffold over time the amount remaining in the scaffold is decreasing in concentration. Thus, in preferred embodiments, drug release from the scaffold is constant, as in zero-order drug release, regardless of concentration of the drug in the scaffold, for at least a portion of the time that the scaffold is implanted within the nasal cavity.

[0567] In fact, an exemplary in vitro release of MF from MF-coated scaffolds (see, Example 15 for additional details) was further determined and is presented in FIG. 39. As shown in FIG. 39, the MF release rate associated with the scaffolds exhibits substantially linear release between 1 and 12 weeks (approximately 90 days) over a 120 day observation period in pH 7.4 PBS buffer containing 2% SDS at 37° C. under gentle shaking. It is noted that release under such conditions has been found to approximately 1.5 to 2 times faster than in vivo release.

[0568] Thus, in some embodiments, the drug release is “substantially linear” or has a “substantially linear release profile”. For example, a substantially linear release profile may be defined by a plot of the cumulative drug release versus the time during which the release takes place, in which the linear least squares fit of such a release profile plot has a correlation coefficient, r.sup.2 (the square of the correlation coefficient of the least squares regression line), of greater than 0.92 for data time points after the first day of delivery (and more preferably after the first month, since the release over the first few weeks can be non-linear), and before 90% of the drug is released. A substantially linear release profile is clinically significant in that it allows release of a prescribed dosage of drug at a substantially uniform rate over an administration period, i.e. a sustained release.

[0569] Zero-order release may be the same as substantially linear, however a zero-order release is actually a constant, e.g. a constant amount of a drug. So likely when the increase in cumulative concentration is constant, as when the slope of the line in a plot of cumulative percent of released drug increases in a straight line, there is also zero-order release of a constant amount of drug. In other words, there is a release of the same amount of drug, i.e. a constant daily dose, regardless of the concentration remaining in the scaffold implant over at least a portion of the time the implanted scaffold is in place.

[0570] For one example, FIG. 39 illustrates initial drug cumulative MF release rates (%) within the first 1-2 weeks and then after around 100 days that do not appear to represent zero-order release as the slope of the line during those time periods is not linear in relation to the straight line over the time in between, i.e. the amount of drug release appears constant.

[0571] Thus, there is a period of time during a 3-month, 4-month, 5-month, or up to a 6-month, of a planned implantation period, where drug release rates are substantially zero-order release, for one example, see constant concentration of MF in the drug plasma amounts over time in a patient shown in FIG. 46A. Illustrative examples of different types of release rates are shown in FIG. 46B. It is expected that plasma drug concentration recorded in a patient having bilateral MF scaffold implants will be linear for over at least a 3-month period or more, indicating a constant daily dose. It has been projected that the implant will deliver a constant daily dose between 1.5 and 4.5 months of at least a 5 month period. FIG. 46C shows projected in vivo release profiles as daily doses of an MF scaffold implant were linear in an experimental study for over at least a 3-month period or more, between 1.5 and 4.5 months of at least a 5 month period. A similar release profile is expected in vivo.

[0572] Thus, it is not intended for the type of drug release to always be zero-order release. It is common that release rates deviate from linear release, for example immediately after implantation or towards the end of a 3-month, or at the end of a 4-month, or at the end of a 5-month, or at the end of a 6-month, planned implantation period.

[0573] In some embodiments, the release of drug from a scaffold is considered a slow release of the drug. In some embodiments, scaffold components modulate the release of the drug. The term “slow” in reference to release of a drug, e.g. where a topcoat layer may slow the release of a drug, also refers to “modulation” of release of a drug.

[0574] Magnetic Resonance Imaging (MRI).

[0575] In some aspects, an Mill image is obtained one or more times, including before implantation (baseline) then at least one time after implantation, for example, an image is obtained at least 4 weeks, 8 weeks, up to 12 weeks or more after implantation. In some aspects, a coronal MM image is used for a comparative assessment of disease volume, amount of swelling and aeration volume.

[0576] Kits.

[0577] In some aspects, the scaffolds described herein may be provided in a kit that includes (a) one or more scaffolds, (b) delivery catheters (applicators), and (c) optional loading aids (e.g., crimping mechanisms), among other components.

[0578] In some aspects, an exemplary kit includes a scaffold termed a 480 Biomedical Mometasone Furoate Sinus Drug Depot (MFSDD). In preferred embodiments, the 480 Biomedical Mometasone Furoate Sinus Drug Depot (MFSDD) is a sterile, bioresorbable corticosteroid depot, designed to deliver anti-inflammatory therapy local to the nasal mucosal tissue of patients diagnosed with Chronic Sinusitis (CS).

Descriptions of Preferred Embodiments

[0579] In some embodiments, patients receiving the implants described herein are without a prior sinus surgery. In one embodiment, patients receiving the implants described herein had prior sinus surgery. In a preferred embodiment, patients receiving the implants had surgical procedures that did not affect the middle meatus.

[0580] In some embodiments, patients receiving the implants described herein have rhinitis. In some embodiments, patients receiving the implants described herein do not have rhinitis.

[0581] In some embodiments, patients receiving the implants described herein are subjected to testing prior to implantation, e.g. a Lund-Mackay score for CT scans of the sinuses. The Lund-Mackay score is a widely used method for radiologic staging of chronic rhinosinusitis. The method is intentionally simplistic, for the sake of minimising interobserver variability and expediting its application. For example, when reading a CT scan of the paranasal sinuses and ostiomeatal complex, the reader assigns each sinus a score of:

[0582] 0 (no abnormality)

[0583] 1 (partial opacification) or

[0584] 2 (complete opacification)

As a further example, the ostiomeatal complex is assigned a score of either 0 (not obstructed) or 2 (obstructed). All of the sinus can be scored in a similar manner. Despite its simplicity, it correlates well with disease severity, extent of surgery, and complication rates, even independent of the extent of surgery. In some embodiments, patients receiving the implants described herein are subjected to testing after implantation, e.g. a Lund-Mackay score for CT scans of the sinuses. In some embodiments, the test scores (before and after implantation) are compared.

[0585] In some embodiments, a synthetic corticosteroid, Mometasone Furoate (MF) is the active ingredient embedded within an inactive bioresorbable carrier to allow for controlled and sustained release of MF delivered from bioresorbable polymers that provide approximately up to six (6) months of drug delivery with a single administration (after nasal insertion). In some embodiments, a scaffold is removed from the middle meatus after implantation, such as after 3 months, after 4 months, or after 6 months.

[0586] Compared to topical MF nasal sprays, an MF scaffold provides targeted drug therapy to inflamed nasal mucosal tissue and does not require patient adherence to topical intranasal sprays, which has been demonstrated to be sporadic. Patient compliance is particularly essential to the success of a medical treatment for chronic conditions.

[0587] In some embodiments, a scaffold has at least 2000 mcg of MF up to 2500 mcg, up to 3000 mcg, up to 3500 mcg of MF, up to 4000 mcg of MF, up to 4500 mcg of MF, up to 5000 mcg of MF.

[0588] In some embodiments, a scaffold is at least 13 mm in diameter. In some embodiments, a scaffold is at least 10 mm in length.

[0589] In some embodiments, a 480 MFSDD scaffold is 13 mm×10 mm (diameter×10 mm). In some embodiments, a 480 MFSDD scaffold has at least 2000 mcg of MF up to 2500 mcg, up to 3000 mcg, up to 3500 mcg of MF, up to 4500 mcg of MF, up to 5000 mcg of MF.

[0590] In some embodiments, a 480 MFSDD scaffold is at least 13 mm×at least 10 mm (diameter×length).

[0591] The 480 MFSDD scaffold is intended to be bilaterally inserted, i.e. one in each nostril, within the middle meatus by an otolaryngologist with the use of an applicator under endoscopic visualization. Once placed, the depot delivers an anti-inflammatory corticosteroid drug in a controlled and sustained manner to the inflamed mucosal tissue from a single administration. The depot is designed to be self-retaining against the mucosa of the middle meatus to allow effective drug transfer to underlying inflamed tissue.

[0592] In some embodiments, a scaffold can be placed and removed easily in the office setting. In some embodiments, a patient with a scaffold implant experiences significant symptom relief by 7 days with a durable effect to at least 12 weeks, up to 16 weeks, up to 3 months, up to 4 months, up to 5 months, up to 6 months and beyond, in duration. In some embodiments, a patient with a scaffold implant was a CRS candidate surgical patient prior to implantation with an MF scaffold converted to a patient no longer requiring surgery (i.e. the patient's symptoms are reduced such that the patient is no longer meets the criteria designating the patient as a surgical candidate).

[0593] In some embodiments, the use of a scaffold as described herein for administering a topical steroid to patients instead of using a topical steroid spray has advantages including: a higher efficiency of scaffold drug access to affected nasal tissue and higher patient compliance with one implant compared to inefficient spray due to nasal obstructions and fast clearance and poor patient compliance to spray schedule. The use of a scaffold has additional advantages over oral steroids as systemic complications limit oral steroid use; over FESS which has an OR procedure, uses general anesthesia, often inducing scar tissue which leads to recurrence of nasal condition, is costly ($10-$25K per patient).

[0594] In some embodiments, a corticosteroid-eluting (mometasone furoate) scaffold implant is termed FBM-210. In some embodiments, a scaffold results in rapid symptom improvement as early as 1 week. In some embodiments, a profound effect is observed by 3 months with ˜70% of patients converted from being surgical candidates to no longer meeting the criteria for surgery. In some embodiments, a FBM-210 scaffold may be used for surgically naïve patients.

[0595] In some embodiments, the use of a scaffold as described herein is further indicated for polyp patients; nonpolyp patients; sustained topical drug treatment for up to 6 months, does not require prior surgery or surgery to administer scaffold. In fact, in some embodiments, use of a scaffold as described herein is a treatment option before or instead of surgery.

Methods of Use

[0596] One embodiment for an implant procedure is provided here, per the exemplary steps below. In some embodiments, at least one or more steps are provided as a package insert for including in a kit comprising a scaffold.

[0597] Pre-Procedure. Apply topical anesthesia (required) and decongestant (optional) per institutional practice to both nasal cavities. Visually inspect middle meatus to confirm that sinonasal anatomy will accommodate the size of the depot (MFSDD) scaffold and associated applicator.

[0598] Preparation of 480 MFSDD scaffold. Prior to removal from package, inspect the product and package to ensure no damage has occurred. Do not use if product or package is damaged.

[0599] This example provides an exemplary method for inserting and use of a scaffold; comprising steps shown in FIG. 49A-D.

[0600] FIG. 49A-D illustrates exemplary steps for inserting a scaffold (depot) into a middle meatus.

[0601] FIG. 49A Exemplary step for inserting a scaffold (depot). Draw the depot into the applicator until the entire depot is visible within the applicator sheath. With appropriate instrument, cut loading assembly about 3 cm from applicator's distal tip (this will release one half of the drawstring sutures).

[0602] FIG. 49B Exemplary step for inserting a scaffold (depot). Hold hub with one hand, and carefully withdraw remaining portion of loading assembly to remove loading sutures from depot.

[0603] FIG. 49C Exemplary step for inserting a scaffold (depot). Carefully remove both the applicator sheath assembly and deployment plunger from the packaging insert. Insert deployment plunger through hole in hub cap.

[0604] FIG. 49D Exemplary step for inserting a scaffold (depot). Advance crimped MFSDD (depot) to distal end of the applicator sheath. The product is ready for introduction into the nasal passage.

[0605] FIG. 49E illustrates a partial deployment of the scaffold from the end of the applicator sheath, outside of nose, merely for illustrative purposes.

[0606] Introduction of 480 MFSDD into Nasal Passage. Using standard endoscopic technique, advance the applicator such that the distal applicator is located at the treatment site (posterior aspect of the middle meatus).

[0607] Depot Deployment. Deploy depot by holding the deployment plunger stationary, and withdrawing the applicator sheath assembly.

[0608] Applicator Removal & Adjustment of 480 MFSDD within the MM. Withdraw applicator to remove it from the nasal cavity, taking caution not to dislodge the depot. If needed, use a freer elevator (or similar tool) to adjust depot position and apposition using direct endoscopic visualization. Once depot placement is complete, remove all surgical equipment from the nasal cavity. Confirm via endoscopy that the middle meatal depot is in place and ensure no bleeding or injury to the mucosa is noted. Dispose of product and packaging per institutional guidelines.

[0609] For treatment requiring bilateral placement, open second depot and repeat above procedure for placement into the second side. Once the overall procedure is completed, determine the patient's well-being and proceed to the end of procedure steps.

[0610] Monitoring Markers. In one embodiment, the implant reduces sinonasal type 2 inflammation as evidenced by suppression of type 2 markers IL-13, CCL26 and Periostin over time. These markers can be used as an indicator of response in a method where these markers are assessed and monitored. In one embodiment, protein concentrations from nasal swabs taken at different time points (e.g. week 0, 4, 12 etc.) are measured using commercially available kits (e.g. a Luminex kit). In one embodiment, expression of mRNAs in nasal swabs at different time points (e.g. week 0, 4, 12 etc.) are assessed by quantitative RT-PCR. Thus, protein and/or RNA markers can be assessed and monitored.

EXPERIMENTAL

Example 1

[0611] Uniformly braided scaffolds (see, e.g. FIG. 3A) were first manufactured using a PLGA(85:15) copolymer by spooling fiber spun monofilaments onto individual bobbins. Each bobbin was placed on a braiding machine, strung through rollers and eyelets and wrapped around a mandrel of desired OD (e.g. 7, 8, or 10 mm). The braiding tension of the machine was set as appropriate for the size of the monofilament. The pix/inch was set to obtain a braid angle with optimal properties including radial strength. The braid pattern was selected and the monofilaments were braided off the spool onto the mandrel by the braiding machine. Tie wraps were used on the end of each mandrel to keep the tension on the filaments, which can be useful for heat annealing and obtaining high modulus properties. The braided polymer was heat annealed on the mandrel, and then cut into desired lengths with a blade and removed from the mandrel.

[0612] The braided PLGA scaffolds were coated with a support coating made from poly(L-lactide-co-ε-caprolactone) (PLCL) cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator with the optional use of a catalyst. In particular, a four-arm hydroxyl terminated PLCL (40:60) (mol/mol), and DD were dissolved in dichloromethane to make a stock solution for spray-coating. The solution was spray-coated onto the braided scaffolds. After thoroughly curing at elevated temperatures, the scaffolds were cut into various lengths for radial force and recovery testing. FIG. 16 shows the macroscopic images of 8 mm, 10 mm, 20 mm and 31 mm scaffolds, each with 16 strands and a braid angle of approximately 100-135 degrees. Some properties of these and analogous scaffolds with different manufactured diameters, numbers of strands, and braid angles are compiled in Table 1 (wherein @[DO-1] mm refers to measurement 1 mm below the manufactured diameter, i.e. 6 mm for the 7 mm scaffolds, 7 mm for the 8 mm scaffolds, and 9 mm for the 10 mm scaffolds).

[0613] All scaffolds have shown excellent diameter recovery (Rec. %) after simulated use. They have variable radial stiffness (RRF and COF) depending on the design.

TABLE-US-00001 TABLE 1 Filament Braid RRF/COF@ Diameter diameter angle Mass [D.sub.0 − 1] Entry (mm) Filaments (in) (deg) (mg/mm) mm (mmHg) Rec. % 1 7 32 0.006″ 127 2.6  492/166 97.9 2 7 24 0.006″ 127 2.1  436/133 98.1 3 7 16 0.006″ 127 1.6 363/66 97.9 4 8 32 0.006″ 127 2.6 431/66 98.8 5 8 16 0.006″ 127 1.6 251/18 99.3 6 10 32 0.006″ 127 2.6 175/30 98.4 7 10 32 0.006″ 110 2.0  54/10 98.6 8 10 16 0.0065″ 127 1.8 99/4 97.4 9 10 16 0.0065″ 110 1.4 31/4 98.6

Example 2

[0614] The scaffolds prepared in Example 1 were further coated with an additional conformal coating comprising a mixture of PLCL and mometasone furoate (MF) as active agent. The PLCL in the MF-containing coating comprised about 70% (mol %) lactic acid, with the balance being caprolactone (PLCL 70:30). A homogenous solution of MF and PLCL was prepared in dichloromethane (DCM). Then, the DCM solution was spray-coated onto a 7 mm scaffold with 24 strands.

[0615] The amount of MF carried by each scaffold was controlled by the thickness and loading rate of the MF-containing coating. By controlling thickness to between <1 μm to um and loading rate from about 1 wt % to about 40 wt % MF relative to total dry coating weight, the inventors have found a drug loading for a 7 mm diameter scaffold to beneficially be about 10 to 2400 μg per 10 mm of scaffold length, more beneficially 100 to 1600 μg per 10 mm of scaffold length. FIG. 17A shows the cumulative MF released in mass for scaffolds with different drug loading rates (5, 10 and 20 weight % corresponding to 100, 200 and 400 μg MF per 10 mm of scaffold length. Significantly, the inventors found that the percentage drug release profiles are marginally affected by the drug-loading rates within a certain range (see FIG. 17B).

Example 3

[0616] To provide more linear release profiles, a topcoat comprising PLCL (70:30) and PLA was further coated onto the drug coated scaffolds. A homogenous solution of 0.75 wt % PLCL and 0.25 wt % PLA was prepared in DCM. Then, the DCM solution was spray-coated onto a 7 mm scaffold with 24 strands in a single coating layer with variable coating passes resulting in different top coat thickness. As shown in FIG. 18, the MF release can be tuned by changing the thickness of topcoat. The thicker is the topcoat, the slower is the drug release. In combination of this approach with different drug loading rate, it is readily to provide different daily dosage with programmable release duration.

Example 4

[0617] Biodegradable polymers such as D,L-PLGA have also be used as the drug carrier. Conformal coatings comprising a mixture of D,L-PLGA and mometasone furoate (MF) as active agent were formed. The coatings contained 20 wt % MF. The D,L-PLGA in the mometasone-containing coating comprised D,L-PLGA having about 50% lactide and 50% ε-caprolactone (50:50) (mol %), D,L-PLGA having about 75% lactide and 25% ε-caprolactone (75:25) or D,L-PLGA having about 85% lactide and 15% ε-caprolactone (85:15). In each case a homogenous solution of MF and D,L-PLGA was prepared in anisole/ethyl formate (50:50 v/v). Then, the solution was spray-coated onto a 7 mm scaffold with 24 strands.

[0618] As exemplified in FIG. 19, the drug released from the scaffolds with these polymers as the coating layer is drastically slower than that coated with PLCL(70:30). In the case of D,L-PLGA, and without wishing to be bound by theory, the drug release is most likely controlled by the degradation of the carrier polymer, with drug molecules to be released in a later stage after the polymer starts to degrade.

[0619] In this context, a scaffold with dual layers of drug coating can be manufactured to achieve sustainable release of MF over a long period of time. For example, a top layer comprising PLCL(70:30) and MF may be formed over a bottom layer comprising DL-PLGA and MF. Without wishing to be bound by theory, in the early stage, it is believed that drug released would be dominated by the diffusion-controlled release of MF from the top layer, whereas in the later stage, the drug in the bottom layer would be released in association with the degradation of DL-PLGA.

Example 5

[0620] A scaffold consisting of 16 monofilament strands (0.0065″ filament diameter, PLGA 85:15) was braided onto a large diameter mandrel (3.175 cm) in a 1×1 braid pattern at 25 picks per inch. The scaffolds were then annealed at 130° C. for 24 hours, cut to a working length and then placed onto fixtures in preparation for spray coating.

[0621] An elastomer solution was prepared using 5 wt % PLCL(40:60) dissolved in DCM. A crosslinker, hexamethylene diisocyanate (45:1 NCO:OH) and zinc octoate catalyst (0.1 wt %) were added to the final solution. The elastomer solution was spray coated onto the scaffold and cured at 100° C. for 24 hrs in an open vial. A photograph of one stent produced in this matter is shown in FIG. 20A and a photograph of a coating node of such as stent is shown in FIG. 20B.

[0622] A flat plate compression test was conducted to assess the mechanical performance of the scaffold post curing. The scaffold was compressed longitudinally up to 50% of the initial diameter. The results are shown in FIG. 21, wherein compressive load is per unit length of the scaffold.

Example 6

[0623] A multifilament strand was prepared by twisting two 0.007″ PLGA 85:15 monofilament strands together. The multifilament strand was then hand woven using a fixture into a variety of braid patterns. An example of the fixture used to prepare multifilament scaffold is shown in FIG. 22. The fixture was also used to prepare scaffolds using monofilament strands. After weaving, filament ends were secured to the fixture using tape and subsequently annealed at 100° C. overnight to set the filaments and maintain filament cross-over points. Scaffolds were then spray coated using an elastomer solution containing 5 wt % PLCL 40:60, HDI (45:1 NCO:OH) and zinc catalyst (0.1 wt %) in methylene chloride. All scaffolds were cured at 100° C. for 24 hrs in an open vial.

[0624] Table 2 contains data generated from five different braid patterns (shown in FIGS. 22A-22E) after spray coating. All scaffolds were measured for diameter, weight, braid angle, acute recovery and recovery post deployment.

TABLE-US-00002 TABLE 2 Twisted multifilament Monofilament 4 filament 2 filament 4 filament 4 filament low braid 2 filament low braid braid braid angle braid angle Device See FIG. 22A See FIG. 22B See FIG. 22C See FIG. 22D See FIG. 22E Mass/length 3.8 5.5 10 2.9 3.8 device (mg/mm) Mass (mg) 77.0 ~110 203 57.4 76.6 Braid angle ~75 ~70 ~45 ~80 ~50 Device diameter ~38 ~38 ~38 ~38 ~38 (mm) Acute recovery 83% 60% Buckled 78% 85% Recovery (>10 85% 68% (non-circular 90% 85% mins post-deploy) recovery)

[0625] Recovery testing was performed by crimping and transferring the scaffolds through a series of large to small tubes using an outer braided mesh sheath until a crimp diameter of 4-5 mm was reached. The acute recovery and post deployment recovery is reported as a percentage of the initial diameter.

Example 7

[0626] In vivo performance of a scaffold in accordance with the present disclosure was examined within a swine cadaver. This study utilized a scaffold in accordance with the present disclosure, approximately 7 mm in diameter and having a 32 filament braid (ref. Table 1, entry 1), and delivered through a 7.5F catheter.

[0627] The device was implanted into folds of the nasal turbinate of a swine cadaver. The scaffold deployed in the swine nasal cavity in a smooth, controlled fashion by withdrawing the device outer sheath while holding a middle pusher in place. FIG. 23A, FIG. 23B, FIG. 23C and FIG. 23D are photographs illustrating the deployment process. The delivery catheter was approximately 2.8 mm in diameter. The scaffold expanded to fill the space between the nasal septum and a nasal turbinate as seen in FIG. 24.

[0628] These deployments identified some potential benefits of the scaffolds of the present disclosure, including: (a) controlled, accurate delivery, (b) improved apposition/conformability to nasal cavity walls and (c) reduced device profile.

Example 8

[0629] A human cadaver study was conducted to assess the clinical performance of scaffolds in accordance with the present disclosure in the human anatomy. Device prototypes and delivery system prototypes were integrated to test multiple scenarios within the representative anatomy, both before and after functional endoscopic sinus surgery. Endpoints included visual appearance via endoscopy and clinical feedback.

[0630] Several small diameter scaffold prototypes in accordance with the present disclosure are described in Table 1, while two large diameter scaffold prototypes are described in Table 3.

TABLE-US-00003 TABLE 3 Filament Braid Number Load at 50% Mass Diameter Length diameter angle of compression % Design (mg) (cm) (mm) Filaments (in) (deg) scaffolds (N) Recovery 2 filament 60 ~3.8 20 2 0.0075″ 50 1 0.034 85 braid offset twisted 4 filament 77 ~3.8 20 4 0.0075″ 70 1 0.032 85 braid (monofilament)

[0631] Scaffolds formed using procedures along the lines described in Example 1 were placed in the middle meatus, providing mechanical force to displace the middle turbinate medially and demonstrating the potential to deliver drug to the ethmoid sinuses. Five deployments were conducted: (a) a 16 filament, 8 mm scaffold, (b) a 32 filament, 8 mm scaffold, (c) a 16 filament, 10 mm scaffold, (d) a 32 filament, 10 mm scaffold and (d) a 32 filament, 13 mm scaffold. Although all devices conformed relatively well to the tissues, displacing the middle turbinate medially (MT) and providing outward force on the uncinate process (UP) laterally, the 32 filament, 13 mm scaffold appeared to provide the best fit for the particular space into which it had been implanted. FIG. 25, is a photograph illustrating the 32 filament, 13 mm scaffold (length of 10 mm) following deployment in the middle meatus of a human cadaver. The implant conformed well to the tissues with appropriate medialization of middle turbinate.

[0632] Devices in accordance with the present disclosure were also placed in the frontal recesses of human cadavers. In a first cadaveric specimen, the frontal recess could not be accessed prior to surgical intervention. The ostia to the frontal sinus was approximately 1 mm in diameter and could not accommodate the delivery device. Functional endoscopic sinus surgery (FESS) was conducted to remove ethmoid cells and expand the passage to the frontal sinus. Following this procedure, 32 filament (Table 1, entry 6) and 16 filament (Table 1, group 8) implants were deployed into the fontal sinus ostia. Although both devices conformed well to the tissue, 16 filament device appeared to exhibit enhanced conformance for the particular space into which it had been implanted. FIG. 26 is a photograph illustrating the 16 filament, 10 mm scaffold following deployment in the frontal sinus ostia.

[0633] In a second cadaver, the frontal sinus ostia was accessible prior to surgical intervention. 10 mm, 16 filament implants (n=1 from Table 1, entry 8 and n=1 from Table 1, entry 9) were deployed into the frontal sinus before and after FESS, respectively. These implants conformed well to the sinus ostia.

[0634] A 16 filament, 10 mm diameter scaffold, a 4 filament, 38 mm scaffold, a 2 filament, 38 mm scaffold, and a 32 filament, 17.5 mm scaffold were placed the ethmoid sinus of human cadavers following functional endoscopic sinus surgery, with the 10 mm diameter scaffold appearing to be undersize for the particular space into which it had been implanted, the 38 mm scaffolds appearing to be oversize for the particular space into which it had been implanted, and with the 17.5 mm scaffold appearing to provide the best fit for the particular space into which it had been implanted. FIG. 27, which is a photograph illustrating a 32 filament scaffold having a diameter of 17.5 mm and a length of 10 mm after deployment in the ethmoid sinus following FESS.

[0635] This study utilized 7.5 French and 9 French catheter systems. The 7.5F system was used to access all frontal sinuses, while the 9F system was used for device deployments into the ethmoid sinus. Both catheter diameters were acceptable, and no devices functioned appropriately during use. A 90-degree bend was appropriate for reaching the frontal sinus. Catheters of this type are described, for example, in “SINUS SCAFFOLD DELIVERY SYSTEMS,” Attorney Docket No. 81354800002, Serial No. 62/186,311, filed on Jun. 29, 2015, which is hereby incorporated by reference.

[0636] All devices were easily repositioned using standard tools following deployment. All devices were easily removed from the body.

Example 9

[0637] Uniformly braided PLGA(10:90) or PLGA(75:25) scaffolds (diameter=8 mm, 16 strands, having a braid angle of 120°) were coated with a support coating made from poly(L-lactide-co-ε-caprolactone) (PLCL) cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator and zinc octoate (Zn(Oct).sub.2) as a catalyst. More particularly, four-arm PLCL (40:60), HDI, DD, and Zn(Oct).sub.2 were dissolved in dichloromethane (DCM) to make a stock solution for spray-coating. The solution was spray-coated onto the braided scaffolds using standard procedures. After drying at room temperature under a nitrogen environment overnight, the scaffolds were thoroughly cured at 60° C. and then cut into 10 mm length for radial force and recovery testing. To improve the node accumulation of elastomer on the scaffolds, anisole (AN) was used as a co-solvent in the spray-coating solution. After drying and curing treatment as described above, these scaffolds were also subject to mechanical performance evaluation. FIGS. 28A-28D are optical microscopic images of coated 8 mm scaffolds having 16 strands with and without anisole as a co-solvent during spray-coating as follows: FIG. 28A, PLGA(10:90) scaffold without anisole co-solvent; FIG. 28B, PLGA(10:90) scaffold with anisole co-solvent; FIG. 28C, PLGA(75:25) scaffold without anisole co-solvent; and FIG. 28D PLGA(75:25) with anisole co-solvent. Some properties of these scaffolds are compiled in Table 4.

TABLE-US-00004 TABLE 4 Rec. % of Base braid Solvent for Wt % of RRF/mmHg COF/mmHg initial material coating elastomer (5.5 mm) (5.5 mm) diameter PLGA(10:90) DCM 93 70 21 98.4 PLGA(10:90) DCM/AN 95 151 65 98.5 PLGA(75:25) DCM 98 70 24 98.8 PLGA(75:25) DCM/AN 96 139 77 99.6

[0638] All scaffolds showed excellent diameter recovery after simulated deployment. However, the scaffolds have drastically different radial stiffness depending on the node accumulation of elastomer. The base braid material does not significantly impact the radial stiffness of the coated scaffolds as these two materials have comparable modulus. Similarly, 22 mm diameter PLGA(10:90) scaffolds were coated with the same elastomer in the absence and presence of anisole as a co-solvent during spray-coating as described above. The scaffolds have 32 strands and a braid angle of 128 or 140. FIGS. 29A-29C show optical images of coated scaffolds with and without anisole as a co-solvent during spray-coating as follows: FIG. 29A scaffold coated with 62 wt % elastomer relative to the weight of the base braid (i.e., the ratio between the mass of the elastomer and the mass of the base braid) from solution that does not contain anisole as a co-solvent; FIG. 29B scaffold coated with 63 wt % elastomer relative to the weight of the base braid from solution containing anisole as a co-solvent; and FIG. 29C scaffold coated with 100 wt % elastomer relative to the weight of the base braid from solution containing anisole as a co-solvent. As above, the presence of anisole during scaffold coating improves the node accumulation of the resultant elastomer on the scaffolds. In addition, more coating material would lead to further node accumulation. To evaluate their mechanical performance, these 22 mm diameter scaffolds (Length=10 mm) were subject to compression test in between two parallel flat aluminum plates assembled onto an INSTRON equipment. The scaffolds were compressed to 75% of their initial diameter and the forces at the compression and the rebound stages were recorded as a function of the compressive distance. Table 2 summarizes the compression force (Fc) and the rebound force (Fr) at 50% compression. These forces are normalized to the scaffold length.

TABLE-US-00005 TABLE 5 Rec. % of Braid Solvent for Wt % of Fc/mN mm.sup.−1 Fr/mN mm.sup.−1 initial angle coating elastomer (50% compression) (50% compressor) Diameter 128 DCM 62 7.6 5.2 94.8 DCM/AN 63 14.7 10.3 96.5 DCM/AN 100 14.7 10.3 96.8 140 DCM 87 15.5 10.8 98.1 DCM/AN 82 18.9 12.6 98.5 DCM/AN 118 20.8 13.4 —

[0639] It is noted that higher braid angle provides higher compression and rebound force of the scaffold. On the other hand, the node accumulation of the elastomer helps to enhance the stiffness of the scaffolds. However, it has been found that further increasing the quantity of the coating material only marginally improves the compression strength of the scaffolds once a certain level of materials has been introduced onto the nodes.

Example 10

[0640] In this Example, scaffolds were further coated with an additional conformal coating comprising a mixture of PLCL and mometasone furoate (MF) as active agent. The PLCL in the MF-containing coating comprised about 70% (mol %) lactic acid, with the balance being caprolactone (PLCL 70:30). A homogenous solution of MF and PLCL was prepared in ethyl formate and anisole (50:50 v/v). Then, the solution was spray-coated onto a scaffold of d=10 mm with 16 strands or a scaffold of d=22 mm with 32 strands. The amount of MF carried by each scaffold was controlled by the thickness and loading rate of the MF-containing coating. In the case of 10 mm scaffolds, drug layers containing 20 wt % MF (80 wt % PLCL) and 40 wt % MF (60 wt % PLCL), respectively, have been coated onto the scaffolds to afford 240 μg and 590 μg MF per scaffold, respectively. In another case, 800 pg MF has been coated onto a 22 mm scaffold with 20 wt % MF (80 wt % PLCL) in the drug layer. The drug layer of these 22 mm and 10 mm scaffolds has comparable thickness.

[0641] The in vitro release of MF from these MF-coated scaffolds was determined. Each scaffold was incubated in a pre-defined amount of pH 7.4 PBS buffer with 2% SDS at 37° C. under gentle shaking. At each indicated time point (see FIGS. 30A and 30B), the buffer was removed completely for quantification of MF by HPLC and new buffer was added. FIGS. 30A and 30B illustrate respectively cumulative absolute and percent mass of MF released from these three sets of scaffolds. As expected, the amount of MF released daily depends on the total MF loading in the scaffolds. On the other hand, the 10 mm scaffolds with 40 wt % MF loading rate exhibit significantly slower percent release than their analogs with 20 wt % MF loading rate. This result is different from what the present inventors have observed for scaffolds with relatively low MF loading rates (e.g. from 5 wt % to 20 wt %). It is hypothesized that the high loading rate of MF in the drug coating layer may result in crystallization of MF, consequently leading to slower drug release. In this regard, tailoring drug crystal size is a method of choice to get control over the drug release profile. Interestingly, the 22 mm and 10 mm scaffolds with 20 wt % MF loading rate show essentially identical percent releasing profiles, suggesting that the releasing profile is barely affected by the dimension of the scaffolds when the drug layer has similar thickness.

Example 11

[0642] Scaffolds of PLGA (10:90) carrying 590 μg MF and scaffolds of PLGA (75:25) carrying 530 μg MF were manufactured at a diameter of 10 mm and length of 6.5 mm. These scaffolds were sterilized using ethylene oxide and implanted into the left and right maxillary sinus cavities of healthy young, 4-6 month old New Zealand white rabbits. Scaffolds were explanted at 3, 7, 14, and 28 days and analyzed for residual drug content using HPLC-UV. Kinetic drug release (KDR) profiles were generated by subtracting the residual drug from the initially loaded drug determined gravimetrically. The tissue that surrounded the scaffold while deployed was collected and analyzed to obtain the tissue drug concentration. FIG. 31 illustrates the in vivo KDR profiles for MF-coated PLGA(10:90) and PLGA(75:25) scaffolds. FIG. 32 shows the MF concentration in the sinus mucosa of sacrificed rabbits at given time points. FIG. 33 shows the total amount of MF on the scaffold plus the amount of drug in the sinus mucosa of scarified rabbits at given time points.

Example 12

[0643] Braided PLGA 17.5 mm diameter scaffolds (PLGA 10:90, 32 strands) were coated with a support coating made from poly(L-lactide-co-ε-caprolactone), specifically, L-PLCL (40:60), cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator with the optional use of a Zn(Oct).sub.2 catalyst as described above. Then, an additional therapeutic-agent-containing layer comprising 30 wt % MF and 70 wt % PLCL was further coated onto the scaffold from a homogenous solution of MF and PLCL prepared in ethyl formate and anisole (70:30 v/v) as described above, except that D,L-PLCL(80:20) or D,L-PLCL(90:10) was used as the carrier polymer, rather than L-PLCL(70:30) as described above in Example 10.

[0644] The in vitro release of MF from these MF-coated scaffolds was further determined as described above in Example 10. As shown in FIG. 34, the MF release rate associated with of D,L-PLCL(80:20) (Tg=20° C.) is much faster than that of D,L-PLCL(90:10) (Tg=35° C.). Without wishing to be bound by theory, it is believed that the glass transition temperature (Tg) of the carrier polymer plays an important role in determining the drug release profile. In this regard, in the absence of Tg effects, it would have normally been expected for the copolymer having the least amount of the more hydrophobic monomer (caprolactone), i.e., D,L-PLCL(90:10), to demonstrate the faster release.

Example 13

[0645] Braided PLGA 17.5 mm diameter scaffolds (PLGA 10:90, 32 strands) were coated with a support coating made from poly(L-lactide-co-ε-caprolactone), specifically, L-PLCL (40:60), cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator with the optional use of a catalyst as described above. Then, an additional therapeutic-agent-containing layer comprising 30 wt % MF and 70 wt % polymer material was further coated onto the scaffold from a homogenous solution of MF and polymer material prepared in ethyl formate and anisole (70:30 v/v) as described above, except that in addition to L-PLCL(70:30) as described above in Example 10, the polymeric materials tested further included a blend of PLCL(70:30) and PLGA(75:25) in a 75:25 wt/wt ratio, a blend of PLCL(70:30) and PLGA(85:15) in a 75:25 wt/wt ratio, and a blend of PLCL(70:30) and PLA in a 75:25 wt/wt ratio.

[0646] The in vitro release of MF from these MF-coated scaffolds was further determined as described above in Example 10. As shown in FIG. 35, the MF release rate is reduced when copolymers of higher lactide content are blended into PLCL(70:30). Without wishing to be bound by theory, it is believed that MF release rate decreases with increasing Tg of the polymer that is blended with the PLCL(70:30). In this regard, PLA has the highest glass transition temperature among the three polymers used (PLGA(75:25) Tg˜(approximately) 50° C., PLGA(85:15) Tg 55° C., and PLATg˜60° C.

Example 14

[0647] Uniformly braided PLGA(10:90) scaffolds (diameter=17.5 mm, length=10 mm, 32 strands, having a braid angle of 90° or 128°) were coated with a support coating made from poly(L-lactide-co-ε-caprolactone) (PLCL) cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator with the optional use of a catalyst as described above and further coated with a conformal coating comprising a mixture of PLCL and mometasone furoate as described in prior Example 10.

[0648] To evaluate their mechanical performance, as shown schematically in FIG. 38, these scaffolds 100 were laid on their sides and compressed in between two parallel flat plates 210a, 210b of a compression apparatus 200 in a chamber maintained at 34° C. and 80% relative humidity. Stated differently, scaffolds 100 were placed in a compressed state between two parallel flat plates 210a, 210b such that the axis A of the tubular scaffold is parallel to the parallel flat plates and such that the tubular scaffold 100 is compressed between the parallel flat plates to a point where a distance d between the parallel flat plates is a percentage of the initial unconstrained diameter such that the tubular scaffold has a first minimum width D measured perpendicular to the axis A that is equal to the distance d, when the scaffold 100 is compressed in the compression apparatus 200 The scaffolds were compressed to either 1.5 mm (8.6% of their initial diameter) or 3 mm (17.1% of their initial diameter). On a weekly basis the scaffolds were removed from the compression apparatus and the recovered minimum width D (also referred to as the second minimum width D) of each scaffold was measured both immediately after removal from the compression apparatus and six hours after removal from the compression apparatus. % recovery is calculated by dividing the second minimum width D immediately after removal or 6 hours after removal from the compression plates by the first minimum width D (which is equal to the distance d across the gap between the parallel plates, i.e. D (in mm)/1.5 mm×100 or D (in mm)/3 mm×100.

[0649] In some embodiments, after being maintained in a compressed state for 10 weeks at a distance d that is 8.5% of the manufactured diameter of the scaffold (e.g., a 17.5 mm scaffold compressed to 1.5 mm), and after removal the tubular scaffold 100 from the compressed state for a period of six hours, the first minimum width D of the tubular scaffold (distance d) may recover to a second minimum width D measured perpendicular to the axis that is at least 450% (e.g., 450% to 1000%) of the first minimum width D (theoretical maximum 1166%). In some embodiments, after being maintained in a compressed state for 10 weeks at a distance d that is 17% of the manufactured diameter of the scaffold (e.g., a 17.5 mm scaffold compressed to 3.0 mm), and after removal the tubular scaffold 100 from the compressed state for a period of six hours, the first minimum width D of the tubular scaffold may recover to a second minimum width D measured perpendicular to the axis that is at least 250% (e.g., 250% to 500%) of the first minimum width D (theoretical maximum 583%).

[0650] Results for the 90° and 128° braid angle scaffolds compressed to 1.5 mm immediately after removal is presented in FIG. 36A and results for the 90° and 128° braid angle scaffolds compressed to 3.0 mm immediately after removal is presented in FIG. 36B. As can be seen from FIG. 36A, the immediate recovery of 90° braid angle scaffolds from 1.5 mm compression is approximately 230% after 1 week and approximately 250% after 10 weeks. The immediate recovery of 128° braid angle scaffolds from 1.5 mm compression is approximately 175% after 1 week and approximately 190% after 10 weeks. As can be seen from FIG. 36B, immediate recovery of 90° braid angle scaffolds from 3.0 mm compression is approximately 165% after 1 week and approximately 170% after 10 weeks. The immediate recovery of 128° braid angle scaffolds from 3.0 mm compression is approximately 140% after 1 week and approximately 175% after 10 weeks.

[0651] Results for the 90° and 128° braid angle scaffolds compressed to 1.5 mm, 6 hours after removal, is presented in FIG. 37A and Table 6, and results for the 90° and 128° braid angle scaffolds compressed to 3.0 mm, 6 hours after removal, is presented in FIG. 37B and Table 7. The 6 hour recovery of 90° braid angle scaffolds from 1.5 mm compression was approximately 540% after 1 week and approximately 510% after 10 weeks. The 6 hour recovery of 128° braid angle scaffolds from 1.5 mm compression was approximately 550% after 1 week and approximately 480% after 10 weeks. The 6 hour recovery of 90° braid angle scaffolds from 3.0 mm compression was approximately 280% after 1 week and approximately 270% after 10 weeks. The 6 hour recovery of 128° braid angle scaffolds from 3.0 mm compression was approximately 300% after 1 week and approximately 190% after 10 weeks.

TABLE-US-00006 TABLE 6 1.5 mm Gap - 90 Braid Angle 1.5 mm Gap - 128 Braid Angle 6 hr 6 hr 6 hr 6 hr Recovery Recovery Recovery Recovery (mm) (%) (mm) (%) 1 wk 8.09 539% 8.23 549% 2 wk 5.36 357% 4.43 295% 3 wk 5.74 383% 5.16 344% 4 wk 5.7 380% 5.36 357% 5 wk 6.26 417% 6.5 433% 6 wk 6.08 405% 6.01 401% 7 wk 5.17 345% 4.7 313% 8 wk 6.1 407% 5.89 392% 9 wk 7.2 480% 7.33 488% 10 wk  7.62 508% 7.2 480%

TABLE-US-00007 TABLE 7 3 mm Gap - 90 Braid Angle 3 mm Gap - 128 Braid Angle 8 hr 6 hr 6 hr 6 hr Recovery Recovery Recovery Recovery (mm) (%) (mm) (%) 1 wk 8.49 283% 8.88 296% 2 wk 6.34 208% 5.24 175% 3 wk 6.67 222% 6.15 205% 4 wk 6.65 222% 6.04 201% 5 wk 7.14 238% 6.52 217% 6 wk 6.81 227% 6.47 216% 7 wk 6.23 208% 6.26 209% 8 wk 7.12 237% 8.09 270% 9 wk 7.65 255% 6.64 221% 10 wk  8.2 273% 5.61 187%

[0652] As can be seen from FIG. 37A, recovery of 90° braid angle scaffolds from 1.5 mm compression appears to be similar to recovery of 128° braid angle scaffolds from 1.5 mm compression at all time points, with each showing a substantial drop in recovery between 1 week and 2 weeks. Representative recovery data is provided in Table 6.

[0653] Likewise, as can be seen from FIG. 37B, recovery of 90° braid angle scaffolds from 3.0 mm compression appears to be similar to recovery of 128° braid angle scaffolds from 3.0 mm compression out to 7 weeks, with each showing a substantial drop in recovery between 1 week and 2 weeks. Representative recovery data is provided in Table 7.

Example 15

[0654] Braided PLGA 13 mm diameter scaffolds (PLGA 85:15, 32 strands) were coated with a support coating made from poly(L-lactide-co-ε-caprolactone), specifically, L-PLCL (40:60 mokmol), cured with hexamethylene diisocyanate (HDI) in the presence of 1-dodecanol (DD) as a chain terminator with the optional use of a Zn(Oct).sub.2 catalyst.

[0655] Then, a therapeutic-agent-containing layer comprising 30 wt % MF and 70 wt % PLCL(70:30 mokmol) was coated onto the scaffold from a homogenous solution of MF and PLCL(70:30) prepared in ethyl formate and anisole. Finally, a topcoat layer of 75 wt % PLCL(70:30) and 25 wt % polylactide (PLA) was further coated onto the scaffold from a solution of PLCL(70:30) and PLA prepared in methylene chloride.

[0656] The in vitro release of MF from these MF-coated scaffolds was further determined and is presented in FIG. 39. As shown in FIG. 39, the MF release rate associated with the scaffolds exhibits substantially linear release between 1 and 12 weeks in pH 7.4 PBS buffer containing 2% SDS at 37° C. under gentle shaking. It is noted that release under such conditions has been found to approximately 1.5 to 2 times faster than in vivo release.

[0657] Although various embodiments are specifically illustrated and described herein, it will be appreciated that modifications and variations of the present disclosure are covered by the above teachings and are within the purview of the appended claims without departing from the spirit and intended scope of the disclosure. For example, while the scaffolds are described herein for sinus applications, such scaffolds may also be useful for other applications such as Eustachian tube stenting.

Example 16

[0658] Twenty patients with symptoms of chronic rhinosinusitis were given implants bilaterally that gradually released mometasone furoate to local tissues over 24 weeks. Nasal swabs and the 22-item Sino-nasal Outcome Test (SNOT-22) questionnaires were collected at baseline (week zero) and at 4 and 12 weeks after implant placement. Protein concentrations in nasal swabs were measured by Luminex kits. Results are presented in FIG. 50 as mean±SEM. * p<0.05, ** p<0.01 and *** p<0.001 by the Wilcoxon matched-pairs signed rank test compared to baseline. Sinonasal proteins of type 2 markers IL-13, CCL26 and Periostin, were found to be suppressed over time after implantation as indicated by their reduced levels when compared to baseline (e.g. the starting point). Type 1 marker IFN-g, and type 3 markers, IL-17A and IL-23, were not affected (data not shown).

[0659] mRNA from nasal swabs at Baseline (week 0) (n=20), 4 weeks (n=11), and 12 weeks (n=9) was also assessed in these patients by quantitative RT-PCR. Results are shown in FIG. 51. Only paired samples at 4 weeks and 12 weeks met RNA quality test. Gene expression levels are shown as % expression of a housekeeping gene, b-glucuronidase (GUSB). Results are presented as mean±SEM. *** p<0.001 by the Wilcoxon matched-pairs signed rank test. Sinonasal messenger RNAs of type 2 markers CCL26, Periostin, and CLC, were found to be suppressed over time after implantation as indicated by their reduced levels when compared to baseline (e.g. the starting point). Type 1 markers, CXCL9 and CXCL10, were not affected (data not shown).

Example 17

[0660] The following examples are provided for protein and RNA analysis. The follow abbreviations are used herein: D=Day, e./g. D1 (Day 1); D56 (Day 56), Delta=change; Fold=fold change; T2 (T-helper cell type 2 inflammation) markers, PK=Pharmacokinetic, RIN=Quality of RNA.

Protein Analysis

[0661] As one nonlimiting example, Lyra (LYR-210) PK protein swab samples were taken from the right side of patients' noses. For protein extraction the swabs were placed in 120 ul of a solution containing a protease inhibitor/PBS (phosphate buffered saline). 48 swab samples were evaluated by Luminex Assay technology, a type of immunoassay that measures multiple analytes in one sample. Eight Type 2 markers were found based on P1 (phase 1) results using 2 different kits: Millipore high sensitivity kit: IL-4; IL-5; IL-13; IL-21. R&D regular kit: CCL18 (PARC); CCL24 (Eotaxin-2); CCL26 (Eotaxin-3); Periostin. Data was collected using 2 types of swabs; a liquid absorbing swab and a nonliquid absorbing swab, such as used in RNA collection. Exemplary results described and shown herein.

[0662] FIG. 52 Lyra (LYR-210) PK protein swab samples. Received samples=Total 98 protein swabs: 50 D1 (Day 1) samples (24 donors). 48 D56 (Day 56) samples (24 donors). Two D1 protein swabs used for RNA (did not use for protein assays). 48 swabs were from right side of nose: Protein extraction: Add 120 ul Protease inhibitor/PBS. 48 swab samples were used in Luminex assays. Eight Type 2 markers were found based on P1 (phase 1) results using 2 different kits: Millipore high sensitivity kit: IL-4; IL-5; IL-13; IL-21. R&D regular kit: CCL18 (PARC); CCL24 (Eotaxin-2); CCL26 (Eotaxin-3); Periostin.

RNA Analysis

[0663] As one nonlimiting example, Lyra (LYR-210) PK RNA swab samples were collected: 42 D1 (Day 1) samples (21 donors) and 40 D56 (Day 56) samples (20 donors). (Two swab samples were pooled) for 17 pairs (34 samples). Phase I samples were collected by metal swabs. PK samples were collected by Non-metal swabs. mRNA was extracted using conventional extraction solutions then assessed by quantitative RT-PCR. RNA results that met an internal quality test are shown herein. Gene expression levels are shown as % expression of a housekeeping gene, b-glucuronidase (GUSB).

TABLE-US-00008 RNA Quality RIN RNA sample >7 18 5-7 12 <5 4 RNA Quality (17 Pair) RIN Pairs >7 5 >5 13
FIG. 64A Swabs were different between Phase I and PK (Pharmacokinetic) study. Left: Phase I Metal swab. Right: PKNon-metal swab.
FIG. 64B RNA swab assays for T2 markers in PK study. PK study plan.
FIG. 64C Phase 1 results. Sinonasal messenger RNAs of type 2 marker, CCL26, Periostin, and CLC, were suppressed by LYR-210. Type 1 markers, CXCL9 and CXCL10, were not affected by LYR-210. Expression of mRNAs in nasal swabs at Baseline (week 0) (n=20), 4 weeks (n=11), and 12 weeks (n=9) were assessed by quantitative RT-PCR. Results show only paired samples at 4 weeks and 12 weeks that met RNA quality test. Gene expression levels are shown as % expression of a housekeeping gene, b-glucuronidase (GUSB). Results are shown as mean±SEM. *** p<0.001 by the Wilcoxon matched-pairs signed rank test.

[0664] Although various embodiments are specifically illustrated and described herein, it will be appreciated that modifications and variations of the present disclosure are covered by the above teachings and are within the purview of the appended claims without departing from the spirit and intended scope of the disclosure.