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Biologics Feature

Courtesy of Tissue Regeneration Systems

Coating More Valuable than Implant?

Robin Young • Wed, May 31st, 2017

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Hiding in plain sight is the coating—improving bone integration and cutting infection rates, at a cost of mere pennies per implant.

The right coating on a PEEK (polyetheretherketone) implant can stimulate bone growth rates that rivals titanium with BMP (bone morphogenetic proteins).

Another coating can transform titanium into an infection resistant implant.

But a new generation of surface modification technologies are on the verge of creating such a value proposition that one could argue surgeons should pick the coating before the implant.

Infections

The biggest healthcare related complication in the world is healthcare-acquired infections (HAI). Six hundred million patients worldwide (4.1 million patients in Europe and about 1.7 million patients in the United States) fall prey annually. The most common HAIs are surgical site infections (SSIs).

Hip and total knee prostheses account for about 2% of all SSIs. Trauma implants or implants for fracture fixation and stabilization - like plates, screws and stabilizing frames - have an even higher risk for infection since they’re placed into complex, and often open fractures.

Finally, in a cruel twist of fate, slathering antibiotics on every metal, polymer or biologic surface contributes to new strains of anti-biotic resistant bacteria.

Race for the Surface

The instant an implant settles into place, planktonic bacteria migrate onto the newly introduced titanium, stainless steel or polymer surface.

They adhere. Divide. And, dangerously, encapsulate into a polysaccharide layer to protect against the patient’s natural immune response. This layer also shields the bacteria from antibiotic treatment.

Soon, a biofilm forms and the bacteria establish colonies and expand. When the bacterial load reaches critical mass it explodes, sending planktonic bacteria into surrounding tissue.

And…the patient returns to her surgeon with an infection, local bone resorption, bone loss and implant loosening.

On the other hand, osteoblasts might somehow beat planktonic bacteria to the surface. After adhering to the newly introduced implant surface, they divide, creating a collagen matrix. Calcification of the collagen matrix sets up bone apposition on the implant surface.

If that happens fast enough, planktonic bacteria can’t get a foothold.

What will be first? Planktonic bacteria or osteoblasts?

It’s a race for the surface.

Releasing and Non-Releasing Coatings

For the last three decades, manufacturers have employed a coating strategy to help surgeons win the race to the surface.

These coating strategies can be characterized as either releasing or non-releasing.

Non-releasing coatings (like hydroxyapatite) are applied by thermal-processes and are intended primarily to accelerate bone attachment and ingrowth.

Releasing coatings (like antibiotic-containing coatings) are mostly applied by dip or spray coating and attack the infection issue directly.

Since early tissue integration can also reduce infection risk, coatings that promote tissue integration are a two-fer. Hydroxyapatite (HA), which promotes tissue integration, was a huge leap forward in coating technology when it was first introduced in the late 1980s for this very reason.

Long-term studies have shown that uncemented HA-coated implants have a comparable if not superior infection fighting capability to antibiotic-releasing bone-cement encased implants. HA-based coatings (and their derivatives) are the most frequently used implant coatings in the field of orthopedic surgery and trauma today.

That may be about to change.

The Future: Surface Modification

New research into surface chemistry, roughness and crystallinity has opened up new vistas for implant manufacturers to dramatically (like by 1,000 fold) improve an implant’s infection resistance and Osseointegration.

In fact, so revolutionary are these new technologies that the nomenclature should change from “coatings” to “surface modification.”

Here’s a quote from a 2009 paper which appeared in the August, 2009 edition of the journal Biomaterials[1]:

“…altering surface roughness of an implant material from one that possesses conventional, micron size features to one that possesses nanometer size features has been shown to enhance certain cellular, such as osteoblasts (bone-forming cells), adhesion and subsequent cellular functions (such as calcium deposition) while simultaneously decreasing competitive cell, such as fibroblast (cells that create the fibrous tissue around an implanted material preventing proper bone integration) function. Research has specifically demonstrated that nano-rough Ti (created through electron beam evaporation) and nano-tubular and nano-textured Ti (created through anodization) can enhance osteoblast adhesion and other functions (such as alkaline phosphatase synthesis, calcium deposition, and collagen secretion) compared to their micron nano-smooth counterparts. Increased select protein adsorption on such Ti surfaces containing nano-features has been correlated to the improved functions of osteoblasts. Previous studies have also shown that by varying the surface roughness of a biomaterial, bacteria adhesion decreases. However, more research is required to understand the underlying factors for such a phenomenon and translating such results to metals commonly used in orthopedics."

Notice the key word “nano”? As in nano-tubular or nano-rough.

Another paper, this one published just three months ago (February 9, 2017) in the International Journal of Nanomaterials, expanded on the themes mentioned in 2009 and articulated a revolutionary concept – engineered topographical geometries at the nano-level. Here’s a short excerpt:

“It is now well established that nano-scale surface features incorporated into orthopedic implants improve bone growth and reduce bacterial adherence, but it is unknown exactly how the shape or structure of the texture affects bone growth and bacterial inhibition.”

“Lorenzetti et al used hydrothermal treatments to generate nano-rough surfaces on titanium and found that macro- and micro scale grooves (results of the ini­tial material machining process) provided niches for bacteria to adhere and proliferate on, despite high roughness values.”

“We hypothesize that in addition to being nano-rough, it is important for implant surfaces to have specific geometries designed to efficiently prevent bacterial adhesion and growth while still promoting healthy osteoblast (bone-forming cell) growth and activity.”

“When creating nano-rough surfaces, the typical goal has been to aim for specific roughness parameters to prevent bacterial adhesion, proliferation and biofilm formation. However, this approach may not be adequate.”

And a Start-Up Shall Lead the Way

In 2008, three professors, William L. Murphy, PhD, Stephen Feinberg, DDS, MS, PhD, and Frank La Marca MD, co-founded a company in Plymouth, Michigan – just down the road from the University of Michigan School of Medicine – named Tissue Regeneration Systems (TRS).

Dr. Murphy is the Harvey D. Spangler Professor of Biomedical Engineering as well as Orthopedics and Rehabilitation at the University of Wisconsin, and he is Co-Director of the Wisconsin Stem Cell and Regenerative Medicine Center. He’s published over 150 manuscripts, 10 book chapters, and holds 25 patents.

Dr. Feinberg is Professor, Associate Chair & Director of Research at the University of Michigan Department of Oral and Maxillofacial Surgery. He has authored over 120 publications. Dr. La Marca, now with Henry Ford Allegiance Neurosurgery, was previously a Clinical Assistant Professor in the Department of Orthopedics, and Director of the Surgical Spine Program in the Department of Neurosurgery at the University of Michigan School of Medicine. He has published 24 papers.

These scientists engineered a simple calcium phosphate into a family of 3D, architecturally optimized coatings, which operate at the nano level to win the race to the surface.

Slowly, industry began waking up to TRS' science.

A few have begun to incorporate one or more of TRS’ technologies to create these uniquely effective calcium phosphate nanostructures on nearly any surface – metals, polymer, allograft bone, collagen – to enhance osseointegration, capture and kick-start autologous biologics (so they don’t all wash immediately away), modulate the body’s inflammatory response to an implanted synthetic material and reduce the potential for bacterial attachment (1,000x more resistant to antibiotics).

Getting on the Nano-Geometry Bandwagon

In 2010 Jim Fitzsimmons joined TRS as its President and CEO. Jim was formerly with Archus Orthopedics, Guidant, Eli Lilly and has served on dozens of medical technology company boards of directors. He has been backed over his career by some of the premier investment firms in America including MPM Capital, Kleiner Perkins and InterWest partners.

In 2014 Sharon Schulzki joined as Senior Vice President of Business Development. She was formerly a Vice President with DePuy Synthes Spine, COO at NSpine and COO at MacroPore Biosurgery.

Finally, in addition to Venture Investors, TRS’ founding and lead investor, here’s the list of others who’ve jumped onto the nano-geometry bandwagon: University of Michigan, Wisconsin Alumni Research Foundation, Venture Investors, Michigan Economic Development Corporation and Michigan Accelerator Fund.

In an era when product differentiation may mean the difference between struggling and thriving in a deflationary orthopedic industry, moving from conventional coatings to surface modification may well represent the most value-added, but also least expensive, way to drive improved outcomes and product differentiation in an ever more intensely competitive orthopedic marketplace.

And someday we may be paying $2,000 for the coating and $1,000 for the implant substrate. Crazy, right?


[1] The relationship between the nanostructure of titanium surfaces and bacterial attachment; Sabrina D. Puckett 1, Erik Taylor 1, Theresa Raimondo, Thomas J. Webster* Division of Engineering and Department of Orthopaedics, Brown University, Providence, RI 02917, USA

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