EP-4736898-A2 - NANOFIBER-HYDROGEL COMPOSITES FOR ENHANCED SOFT TISSUE REPLACEMENT AND REGENERATION

Abstract

A composite material can include a gel and at least one nanostructure disposed within the gel. A method for healing a soft tissue defect can include applying a composite material to a soft tissue defect, wherein the composite material includes a gel and a nanostructure disposed within the gel. A method for manufacturing a composite material for use in healing soft tissue defects can include providing a gel and disposing nanofibers within the gel.

Inventors

• MARTIN, RUSSELL
• REDDY, SASHANK
• COLBERT, Kevin
• MAO, HAI-QUAN

Assignees

• The Johns Hopkins University

Dates

Publication Date

20260506

Application Date

20190509

Claims (15)

1. A population of substantially non-spherical microbeads comprising: a functionalized hyaluronic acid network covalently linked to a plurality of fibers having a mean length of less than about 200 micrometers, and a reacted crosslinking agent present prior to crosslinking at a concentration from about 1 mg/mL to about 25 mg/mL, wherein the mean size of the microbeads is within the range of about 50 micrometers to about 300 micrometers along the longest dimension.
2. The microbeads of claim 1 wherein the microbeads are pre-reacted.
3. The microbeads of claim 1 wherein the fibers are collagen fiber.
4. A formulation comprising a population of substantially non-spherical microbeads comprising: a functionalized hyaluronic acid network covalently linked to a plurality of fibers having a mean length of less than about 200 micrometers, and a reacted crosslinking agent present prior to crosslinking at a concentration from about 1 mg/mL to about 25 mg/mL.
5. The formulation of claim 4 wherein the microbeads are pre-reacted.
6. The formulation of claim 4 wherein the fibers are collagen fiber.
7. The population of microbeads or formulation of any one of claims 1 to 6 wherein the functionalized hyaluronic acid comprises acrylated hyaluronic acid, and the crosslinking agent comprises thiolated poly(ethylene glycol), or a derivative thereof.
8. The population of microbeads or formulation of any one of claims 1 to 6 wherein the functionalized hyaluronic acid comprises acrylated hyaluronic acid, and the crosslinking agent comprises poly(ethylene glycol) diacrylate (PEGDA), or a derivative thereof.
9. The population of microbeads or formulation of any one of claims 1 to 8 wherein the microbeads have a mean storage modulus of between about 50 Pa and abut 2500Pa.
10. The population of microbeads or formulation of any one of claims 1 to 8 comprising a plurality of pores.
11. The population of microbeads or formulation of claim 10 wherein the plurality of pores comprises an area density no less than about 50 pores per cm 2 , with at least about 80% of pores having a mean size of no less than about 5 micrometers.
12. A formulation of any one of claims 4 to 11, wherein the microbeads are lyophilized to form a population of dehydrated microbeads, and wherein the dehydrated microbeads are suitable for reconstitution with water, saline solution or suitable reconstitution fluid to substantially replace the water mass lost (as measured by weight) prior to administration into a target tissue of subject such that when the water mass lost is replaced, the concentration of the microbeads in the reconstitution fluid is the same or substantially the same as the concentration of microbeads before lyophilization.
13. A kit comprising a syringe comprising from about 0.1 mL to about 20 mL of the microbeads of any one of claims 1 to 11, wherein the microbeads are formulated as i) substantially dehydrated beads or ii) hydrated beads that are ready for injection into a target tissue of a subject.
14. A method of performing a cosmetic procedure, comprising injecting into the tissue and/or tissue defect a population of microbeads or formulation of any one claims 1to 12 .
15. The population of microbeads or formulation of anyone of claims 1 to 11 for use in performing a reconstructive procedure or reducing or reversing a tissue defect resulting from trauma, surgical intervention, or an age-associated disease, disorder or condition.

Description

This application claims the benefit of U.S. Provisional Application 62/669,307 filed May 9, 2018, which is incorporated by reference herein in its entirety. GOVERNMENT SUPPORT This invention was made with government support under grant no. 1R21NS085714 awarded by the U.S. National Institutes of Health and grant no. DMR1410240 awarded by the National Science Foundation. The government has certain rights in the invention. BACKGROUND Field The present disclosure relates to composite materials and methods that restore lost soft tissue volume while promoting soft tissue regeneration. The present invention also relates to composite materials and methods for cosmetic, and reconstructive purposes. Description of Related Art Soft tissue defects resulting from trauma, oncologic resection, or congenital malformation are difficult to treat by conventional means. Current therapies, including tissue rearrangements or tissue transfer, cause donor site defects. Other therapies, such as prosthetic implants, lead to fibrosis and encapsulation. Existing strategies to promote tissue ingrowth are also inadequate for the treatment of soft tissue defects. Current acellular matrices result in flat, fibrotic sheets of tissue rather than the soft, three-dimensional tissue required for ideal reconstructions. Finally, while fat grafting can restore soft tissue defects, its wider use is hampered by variable graft survival and limited volumes of restoration. An ideal approach to soft tissue reconstruction would encourage regeneration of soft tissues such as adipose tissue in vivo followed by implantation of the tissues to promote regeneration. However, tissue regrowth requires a suitable matrix for cells to attach, migrate, proliferate, differentiation, and organize into new tissue. Much of the native extracellular matrix (ECM) is missing at the repair site. Therefore, recreating a synthetic matrix that not only immediately restores the lost tissue volume, but also reconditions the microenvironment, supports host cell infiltration, and encourages regeneration of soft tissue, becomes an essential task when repairing soft tissue defects using adipose tissue-based reconstruction. Hydrogels have received significant interest as ECM mimics due to their high water content and water-swollen networks that allow for facile transport of water-soluble biomolecules. Therefore, hydrogels offer several advantages as a filler material for soft tissue reconstruction. While several hydrogels have shown some benefits in soft tissue reconstruction, there is no current material that is able to address all of the mechanical challenges in succession. To achieve sufficient mechanical property, higher crosslinking densities are usually required. Under these conditions, however, host tissue cells (e.g., adipocyte progenitors and endothelial progenitors) are not able to penetrate and grow into the scaffolds. In case of degradable hydrogels, scarring and fibrous tissue formation are typical because ingrowth of host tissue occurs too slowly, or at least at a pace slower than the absorption of the fiber material. Recently, functionalized nanofibers have been developed to serve as ECM mimics to support various cell activities. FDA-compliant synthetic biodegradable poly-α-esters, such as polycaprolactone (PCL) or poly(lactide-co-glycolide) (PLGA) can be used to generate nanofibers through a process known as electrospinning. Biodegradable sutures and implants prepared from these polymers have been widely used clinically due to their excellent track record on biocompatibility. Various nanofibers of varying diameters and topographies for stem cell engineering applications have been developed. These nanofibers, however, do not offer macroscopic structures, making them difficult to use as 3D scaffolds. Many commercialized hydrogel fillers cause moderate to severe inflammation in the patient, while not retaining full original volume over time. Given the various problems associated with such conventional methods and systems, there is still a need in the art for improved solutions to healing soft tissue defects. The present disclosure provides a solution for this need that overcomes the various problems noted in the art. SUMMARY The compositions and methods in the following disclosure have been designed to addresses this need by using compositions comprising fiber-hydrogel composites such as fiber-hydrogel composite microbeads that possess improved properties (e.g., improved qualities for reconstruction of soft tissue, as detailed further infra). Thus, in one aspect, disclosed herein is a population of substantially non-spherical microbeads comprising a functionalized hyaluronic acid network covalently linked to a plurality of polycaprolactone fibers having a mean length of less than about 200 micrometers, and a crosslinking agent present at a concentration from about 1 mg/mL to about 25 mg/mL, wherein the mean size of the microbeads is within the range of about 50 micromete