Bringing hydrogel-based craniofacial therapies to the clinic

Abstract

This review explores the evolution of the use of hydrogels for craniofacial soft tissue engineering, ranging in complexity from acellular injectable fillers to fabricated, cell-laden constructs with complex compositions and architectures. Addressing both in situ and ex vivo approaches, tissue restoration secondary to trauma or tumor resection is discussed. Beginning with relatively simple epithelia of oral mucosa and gingiva, then moving to more functional units like vocal cords or soft tissues with multilayer branched structures, such as salivary glands, various approaches are presented toward the design of function-driven architectures, inspired by native tissue organization. Multiple tissue replacement paradigms are presented here, including the application of hydrogels as structural materials and as delivery platforms for cells and/or therapeutics. A practical hierarchy is proposed for hydrogel systems in craniofacial applications, based on their material and cellular complexity, spatial order, and biological cargo(s). This hierarchy reflects the regulatory complexity dictated by the Food and Drug Administration (FDA) in the United States prior to commercialization of these systems for use in humans. The wide array of available biofabrication methods, ranging from simple syringe extrusion of a biomaterial to light-based spatial patterning for complex architectures, is considered within the history of FDA-approved commercial therapies. Lastly, the review assesses the impact of these regulatory pathways on the translational potential of promising pre-clinical technologies for craniofacial applications. STATEMENT OF SIGNIFICANCE: While many commercially available hydrogel-based products are in use for the craniofacial region, most are simple formulations that either are applied topically or injected into tissue for aesthetic purposes. The academic literature previews many exciting applications that harness the versatility of hydrogels for craniofacial soft tissue engineering. One of the most exciting developments in the field is the emergence of advanced biofabrication methods to design complex hydrogel systems that can promote the functional or structural repair of tissues. To date, no clinically available hydrogel-based therapy takes full advantage of current pre-clinical advances. This review surveys the increasing complexity of the current landscape of available clinical therapies and presents a framework for future expanded use of hydrogels with an eye toward translatability and U.S. regulatory approval for craniofacial applications.

Keywords: Biofabrication; Biomaterials; Craniofacial repair; Device approval; Hydrogels; Regulatory path; Soft tissue; Tissue engineering.

Figure 1.

In this figure, the categories of hydrogel systems for craniofacial applications are classified by manufacturing processes, structure and composition, and mechanism of action. In each case, complexity builds from left to right.

Figure 2.

The set of design criteria for a manufacturer of topical hydrogel-based formulations are highlighted. Panel (A) is a schematic of the proposed mechanisms for the skin permeability of hyaluronic acid. [106] High MW HA primarily interacts with the stratum corneum through hydrophobic interactions, while some low MW HA can even permeate into dermis This greatly informs design choices for topical facial applications. (B) is a schematic illustration of the effects of hydrogels in the treatment of selected skin diseases that affect the head and face. [107] These treatments are commercially available as hydrogel formulations that can be topically applied. (C) is a depiction of a typical patient before and after treatment with a combination clindamycin/tretinoin hydrogel for acne vulgaris [96] (D) is a depiction of a range in the apparent viscosity and appearance of lipid-based systems and emulsion for cosmetic applications. Apparent viscosity increases from a water-like liposome solution to a dehydrated film of a stiff gel. [97]

Figure 3.

0^th order hydrogel systems are summarized. (A) depicts a nanofiber-hydrogel composite that mimics soft tissue ECM through covalent interfacial bonding between electrospun PCL fibers and a HA hydrogel. [47] (B) Self-assembling peptide gels represent an injectable option [134], and have been used for mucosal regeneration and are sold commercially under the name PuraStat and PuraSinus. [126] C) Depicts Osmotic tissue expanders, sold under the trade name OSMED, which have been used for soft tissue expansion of the palate cleft. [138] (D) Outlines the design of a thermoresponsive gel for use in patients with ocular trauma. [66]

Figure 4.

1st order hydrogels, which contain a CBER/CDER-regulated biologic, or a function-driven structure, but are manufactured using previously validated methods. (A) Depicts the surgical placement of a collagen patch for dura repair, an early example motivating the need for a current clinical trial for the use of Duragen seeded with ASCs for skull base surgery [155,156] (B) Depicts the mode of action of Biotime’s Renevia®, demonstrating how a living tissue graft is established in vivo. [160] (C) A schematic depicting supramolecular peptide-based hydrogels for dental pulp revascularization. [163] (D) Outlines the development of a decellularized ECM based bioink for auricular reconstruction, a variation of which is currently in clinical trials [167,168]

Figure 5.

2A hydrogel systems, which have a secondary mechanism of action and no need for manufacturing validation, are summarized. (A) depicts stained sections of tissue engineered skin and gingiva formed using collagen gels [183] (B) depicts a biopsy specimen harvested from the mucosa inside a patient’s mouth, as well as the EVPOME construct pre-grafting, which consists of an Alloderm construct seeded with oral keratinocytes. [53] (C) outlines a tissue-engineered human vocal-fold mucosa using a collagen scaffold and demonstrates similarity to native tissue. [190] (D) Depicts GelMA hydrogels infused with vertically aligned carbon nanotubes to support skeletal muscle differentiation and myofiber formation. [194]

Figure 6.

2B hydrogel systems, which have a secondary mechanism of action, and need manufacturing validation, are summarized. (A) This schematic outlines an extrusion-based method of collagen 3D printing with alternating layers of keratinocytes and fibroblasts. [197] (B) A schematic of the approach to alginate-based 3D printing of MSCs along with sweat gland ECM containing growth factors for sweat gland regeneration. [198] (C) This study develops a 3D printed human airway epithelium using thermoresponsive collagen hybrid gel embedded with human bronchial epithelial cells and human bronchial fibroblasts. [199] (D) This depicts 3D-printing of GelMA along with ASCs that secrete neurotrophic factors in a secondary mechanism of action as nerve guidance conduits that promote peripheral nerve regeneration. [200]