The clinical needs
for bone regeneration are diverse, and there are roughly one million patients who have skeletal defects each year in the United States alone, which require bone graft procedures to achieve union.1
Toward this end, tissue engineering approaches have received great deal of attention as promising alternatives to conventional autologous bone grafts that are considered the golden standard for repairing critical-sized bone defects.2,3
Numerous biomaterials have been developed for bone tissue engineering applications ranging from naturally derived materials to synthetic biopolymers.4–8
In the past decades, significant progress has been made to fabricate three-dimensional (3D) porous polymeric scaffolds with controlled morphology and micro-architecture for bone tissue engineering.9
However, most of these techniques such as fiber bonding,10
and phase separation12
are not compatible for use with injectable materials.
It is known that porous scaffolds can also be generated by combining a water-leachable porogen (e.g., sodium chloride) in the injectable paste.13,14
However, there are many issues associated with the use of high salt porogen concentrations. These include difficulty of handling and decreased injectability of the composite, nonuniform distribution of the porogen, compromised mechanical strength of the scaffold after porogen leach-out, and potential local toxicity caused by high osmolarity from the leached salt. For example, previous work demonstrated that the solid salt porogen particles will not flow in a homogeneous manner with the polymerizing scaffold during injection when the porosity reaches above 75%.15
Due to the limited amount of porogen that can be incorporated, it is often difficult to achieve high porosity to induce tissue ingrowth and minimize diffusion limitations for certain type of polymers such as injectable polymers. In addition, once the scaffold is injected, the process of porogen diffusion out of the scaffold needs to occur before the scaffold pores being filled with physiological fluids.
In current study, we propose a novel concept of using hydrogel microparticles (MPs) as porogens to reproducibly form well-interconnected pore networks. Hydrogel MPs are incorporated into the injectable paste, they swell during mixing and injection to retain water in the pores, and instead of leaching out, the porogens create pores as they can degrade in physiological condition. The potential advantages of hydrogel porogens include better rheological properties during injection, eventual elimination of the porogen leaching step, and the ability to load and deliver cells, bioactive molecules, or both within the hydrogel phase at the time of scaffold injection into the defective tissue site.
In this study, we chose poly(
-caprolactone fumarate) (PCLF) as a matrix polymer mainly because it is biocompatible, biodegradable, self-crosslinkable without the use of any crosslinkers, and injectable, and it involves relatively simple and straightforward synthesis process.16
Two different hydrogels were chosen for fabrication of hydrogel porogens: one is gelatin, one of the most widely investigated natural hydrogels for tissue engineering applications, and the other is poly(ethylene glycol) sebacic acid diacrylate (PEGSDA), a novel biodegradable synthetic hydrogel developed in our laboratory.17