Uniaxially-aligned nanofiber scaffolds and methods for producing and using same
Inventors
Goudy, Steven L. • Botchwey, Edward A.
Assignees
Publication Number
US-12263277-B2
Publication Date
2025-04-01
Expiration Date
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Abstract
Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Patients undergoing cleft palate repair have a high degree of wound healing complications, such as oronasal fistula (ONF) formation. Following hard palate injury, ONF was created that demonstrated little change in pro-regenerative monocytes LY6Clo monocytes; however, there were increased M2 macrophages observed. Delivery of FTY720 nanofiber scaffolds following hard palate injury prevented ONF formation, allowed complete wound healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Evaluation of interleukin gene expression revealed reduction in pro-inflammatory IL1 and IL6 and increased expression of pro-regenerative IL10 with FTY720 nanofiber delivery. The ability of FTY720 scaffolds to increase LY6Clo monocytes, increase M2 macrophages and alter the interleukin expression during hard palate mucosal healing demonstrates the ability of a FTY720-based autotherapy to improve oral cavity wound healing.
Core Innovation
The present disclosure relates to medical devices, including scaffolds and methods for using the same, for improved wound healing. The disclosure describes novel approaches for recruitment of pro-regenerative non-classical monocytes using degradable nanofiber scaffolds loaded with immune modulatory drug FTY720 to improve oral cavity, mucosal, and other soft tissue wound healing. The scaffolds are described as uniaxially-aligned nanofiber constructs that locally deliver FTY720 to control the monocyte population that migrates to the wound.
Oral cavity wound healing occurs in a bacteria laden environment that undergoes constant trauma and is exposed to saliva, and poor wound healing following cleft palate repair can occur in up to 60% of patients leading to persistent oronasal fistula (ONF). Persistent ONF causes reflux of liquids from the nose, air escape during speech, and can require additional anesthesia and revision surgeries; the only available regenerative strategies described are donated human material implanted as a barrier, carrying risk of transmissible disease and other complications. Therefore, there is a long-felt but unresolved need for devices and methods that improve wound healing for ONF directly at the wound site by influencing the migration of wound healing cells thereto.
The disclosure describes that delivery of FTY720 nanofiber scaffolds following hard palate injury prevented ONF formation, allowed complete wound healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Evaluation of interleukin gene expression with FTY720 nanofiber delivery revealed reduction in pro-inflammatory IL1 and IL6 and increased expression of pro-regenerative IL10. The ability of FTY720 scaffolds to increase LY6Clo monocytes, increase M2 macrophages and alter interleukin expression during hard palate mucosal healing demonstrates the ability of a FTY720-based autotherapy to improve oral cavity wound healing.
Claims Coverage
This section identifies three independent claims (claims 1, 7, and 11) and extracts the main inventive features recited in those claims.
Uniaxially-aligned nanofiber scaffold geometry
A plurality of nanofibers forming a flat portion having a specified diameter range, wherein all of the nanofibers within the plurality are uniaxially aligned (recited in independent claim 1 and claim 11).
Polymer composition with S1P1 agonist
Each of the plurality of nanofibers comprises polycaprolactone (PCL), poly(lactic-co-glycolic-acid) (PLGA), and an S1P1 agonist; the S1P1 agonist is FTY720 (recited in independent claims 1, 7, and 11).
Differential controlled release profile
The S1P1 agonist is differentially released for controlled release with an initial burst release in the first hours, followed by a delay, and a second phase of release occurring between [procedural detail omitted for safety] following implantation (recited in independent claims 1, 7, and 11).
High initial release configuration
The plurality of nanofibers is configured to release a high fraction of the S1P1 agonist within the initial post-implantation period and a configured fraction after a longer post-implantation period [procedural detail omitted for safety] (recited in independent claims 1 and 7).
Polymer weight-ratio parameter
Each of the plurality of nanofibers comprises PCL and PLGA at a predetermined weight ratio within a recited range and specific exemplary ratios are described [procedural detail omitted for safety] (recited across dependent claims referenced by the independent claims).
Drug loading parameter
Each of the plurality of nanofibers includes the S1P1 agonist at a specified drug:polymer weight ratio in certain embodiments and specific alternate drug:polymer weight ratios are recited as embodiments [procedural detail omitted for safety] (recited in the claims depending from the independent claims).
Loaded scaffold dosage
An embodiment recites that the plurality of nanofibers comprises PCL, PLGA, and a specified microgram amount of an S1P1 agonist as an alternative claimed embodiment [procedural detail omitted for safety] (recited in independent claim 7).
Flat portion disk-like shape
An embodiment recites that the flat portion comprises a disk-like shape (recited in a dependent claim of independent claim 1).
Selective recruitment of regenerative immune cells
The implantable scaffold is configured to selectively recruit LY6Clo monocytes and M2 macrophages to an implantation site or to oral cavity wounds when implanted therein (recited in independent claim 11 and claim 1 embodiments).
The independent claims recite uniaxially-aligned PCL/PLGA nanofiber scaffolds loaded with the S1P1 agonist FTY720, a differential controlled-release regimen for the agonist, specified polymer and loading parameters as claimed embodiments, and scaffolds configured to selectively recruit LY6Clo monocytes and M2 macrophages to improve oral cavity wound healing.
Stated Advantages
Improves oral cavity, mucosal, and other soft tissue wound healing.
Prevents oronasal fistula (ONF) formation and allows complete wound healing and re-epithelialization when delivered to hard palate injury sites.
Increases LY6Clo (anti-inflammatory) monocytes and pro-regenerative M2 macrophages at the injury site.
Reduces expression of pro-inflammatory interleukins IL1 and IL6 and increases expression of pro-regenerative interleukin IL10.
Provides an FTY720-based autotherapy that can improve oral cavity wound healing and reduce or prevent associated functional impairments (as described in the patent).
Documented Applications
Treating an oral wound cavity by implanting a scaffold at an oral cavity wound site of a patient, including prevention and treatment of oronasal fistula (ONF).
Local delivery to recruit pro-regenerative non-classical monocytes (LY6Clo) and M2 macrophages to improve oral cavity, mucosal, and other soft tissue wound healing.
Implantable medical device use of uniaxially-aligned nanofiber scaffolds comprising PCL/PLGA and FTY720 for on-site immunoregenerative therapy during palate wound healing.
Methods for fabricating a wound-healing scaffold as recited in the patent (method claims describe forming polymer mixtures and producing nanofibers by electrospinning) — [procedural detail omitted for safety].
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