Kappa Delta Award winners develop novel biodegradable polymeric scaffolds

For more than a decade, Michael J. Yaszemski, MD, PhD, and his co-investigator Lichun Lu, PhD, have focused on finding novel ways to treat bone defects. Their efforts, detailed in their paper “Osteoinductive injectable degradable polymeric scaffolds for osseous defect repair,” earned them the 2009 Kappa Delta Elizabeth Winston Lanier Award.

“Combining polymeric, metallurgic, and tissue engineering strategies with growth and signaling factors that encourage uncommitted cells to become bone-forming cells will, I believe, enable us to develop additional therapies in our lifetime,” said Dr. Yaszemski.

Drs. Yaszemski and Lu have successfully synthesized a series of biodegradable polymers based on polypropylene fumarate (PPF), polycaprolactone fumarate (PCLF), PPF/PCLF blends, and PPF-co-PCLF copolymers.

“These materials can be manufactured in unlimited supply and the flexibility in their design allows the synthesis of a wide range of polymers with varying mechanical, biologic, degradation, and rheological properties,” he said.

Exciting clinical news on the horizon
Dr. Yaszemski’s musculoskeletal bone and tissue engineering program takes a systematic approach to addressing the problems of both contained trabecular and segmental bone defects.

The strategy for treating contained trabecular bone defects includes “injectable formulations of a polymeric scaffold. It may contain cells and/or bioactive molecules and can fill a defect of arbitrary shape through either an open surgical approach or a minimally invasive percutaneous technique.

“The strategy for treating a segmental skeletal defect includes fitting a polymeric scaffold to the defect either by preparing it preoperatively from a computed tomography scan or magnetic resonance imaging data and solid free-form fabrication.

“It can be molded to fit the defect intraoperatively while the polymer is cohesive, yet soft enough to work into a desired shape,” he explained.

Synthetic polymers: The building blocks
In addition developing synthetic polymers, the investigators have design criteria covering biocompatibility, mechanical properties, degradation, osteoconductivity, osteoinductivity, sterilizability, and handling characteristics.

To be biocompatible, the materials cannot be toxic to local or systemic tissues during polymerization, service life, or degradation.

The mechanical properties—compressive modulus and strength—need to be equivalent to that of the trabecular or cortical bone being replaced.

The scaffold must provide support to protect the tissue in its early stages of healing while “gradual load transfer to the newly formed bone is needed later in the regeneration process to allow bone remodeling,” according to Dr. Yaszemski (Fig. 1).

Scaffolds must also serve as suitable substrates where osteogenic cells can proliferate, differentiate, and secrete osteoid matrix.

“Growth factors released from the scaffold further modulate osteoblastic cell functions and enhance bone formation,” he said.

Recently, the team developed injectable materials that meet many of these criteria. The materials need to be cured—either chemically or through a light source—to have the appropriate mechanical strength and the capability of being injected percutaneously, which may limit their use in deep defects.

To overcome this potential obstacle, the investigators developed a series of polymers capable of crosslinking via chemical redox initiation—allowing for many more choices in polymer handling and processing.

Polymer scaffolds: The base for bone
PPF, developed by Drs. Yaszemski and Lu in 1994, has several of the required properties. It degrades by simple hydrolysis into nontoxic products; its compressive strength is equivalent to trabecular bone, and it did not demonstrate a long-term inflammatory response when implanted subcutaneously in rats. In vitro studies have shown that PPF has osteoconductive properties.

To expand the clinical applications for PPF, the team developed a new biodegradable material—PCLF.

“Because the PCL molecular weight can be easily varied, PCLF offers another degree of freedom to control the crosslinking, mechanical, and degradation characteristics of the polymer network,” explained Dr. Yaszemski.

To provide a wide range of properties that could be adapted to a host of clinical applications, the researchers then developed a series of polymers based on both PPF and PCLF by synthesizing blends or copolymers.

Various ratios of PCLF in the PPF/PCLF blends or PCL in the PPF-co-PCL polymer can be used to get “families of polymers with varied properties,” according to Dr. Yaszemski.

The time a surgeon has to use the material can be changed by using different amounts of crosslinking initiator, accelerator, or a different PCL content in the copolymer.

Dr. Yaszemski envisions creating materials for surgeons that have a whole spectrum of properties. If a certain material is needed, the investigators will not “have to go all the way back to the drawing board” but can change the composition or the amount of the blends or the copolymer.

Powering composites with biomolecules
Incorporating and controlling the delivery of bioactive molecules such as growth factors or cytokines can further improve injectable polymeric composites.

“These molecules allow local modulation of cellular function in the degrading composite and help to guide cellular matrix expression toward the bone tissue phenotype,” stated Dr. Yaszemski.

“Bone morphogenetic proteins (BMPs) are an important class of bioactive molecules that play a central role in bone regeneration. Members of the BMP family can initiate the complete cascade of bone formation, including the migration of mesenchymal stem cells and their differentiation into osteoblasts.

“BMP has been one of the members of this growth factor family that has effected the expression of an osteoblastic phenotype in bone marrow stromal cells in vitro, and its delivery to a bone defect could be beneficial for the induction of a bone regeneration cascade,” he explained.

A key part of the investigators’ work has been developing better control over the release profile of BMP. Rather than simply inserting the molecule at the surgical site, they have incorporated it into microparticles, which enable them to control its location and delivery.

“For example, if the BMP is in a microparticle that is in the wall of the scaffold pore, then that BMP is not going to come out and be available until the scaffold wall degrades a bit,” explains Dr. Yaszemski.

“Because we can predict and design a degradation profile of the scaffold wall, we are able to address a clinical situation, for example, where we expect the scaffold to become filled with vascular tissue in two weeks. At that time, we want to signal the recruitment of bone forming cells from the surrounding tissues to the scaffold, so they will anchor to it and begin to build bone.

“By choosing the material and the geometry of the microparticle and the biomolecule in the pores or walls of the scaffold, we have a wide spectrum of control over when that BMP or other molecule is released and becomes available,” he said.

Fueling the BMP-2 engine
Because vascular endothelial growth factor (VEGF) and BMPs are “key regulators of angiogenesis and osteogenesis during the bone regeneration, we investigated if their sequential release could enhance the BMP-2 induced bone formation,” Dr. Yaszemski said.

To determine this, they designed and compared four scaffolds with different properties. “Three-dimensional micro-CT reconstructions revealed vessel formation directly around the implants as well as a significantly higher amount of bone in the VEGF/BMP-2 releasing scaffold compared to scaffolds loaded with BMP-2 alone,” he said (Fig. 2).

The challenges ahead
One of the most significant challenges Dr. Yaszemski faces is ensuring that he has a team whose skills span the entire spectrum needed to get these ideas to patient care.

“I think that continuing to have good communication among all the parties—from the chemists, the cell biologists, the clinicians, to our industry and regulatory partners—is very attainable.

“It takes effort to get everyone who has a question—regardless of which end of the spectrum they’re on—to be able to talk to the person who can answer their question. It takes a team,” Dr. Yaszemski concluded.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org