The recent announcement that Renovos Biologics Ltd. received FDA Breakthrough Device designation for its synthetic nanoclay bone fusion gel, RENOVITE® BMP-2, is the latest in a string of announcements regarding novel delivery scaffolds for BMP-2 (bone morphogenic protein 2) based bone grafts.
In April 2023, the Maryland Tech Council announced that Frederick, Maryland-based Theradaptive, Inc. won the Emerging Life Sciences Company of the Year award for its calcium based, BMP-2 delivery platform and for receiving THREE Breakthrough Device designations from the FDA in 2022.
Then, in May 2023, UK-based Locate Bio Limited announced that the U.S. Food and Drug Administration (FDA) had granted its BMP-2 based bone graft product, LDGraft, Breakthrough Device designation. LDGraft is a novel osteoconductive scaffold which provides controlled and extended release of recombinant human bone morphogenetic protein 2 (rhBMP-2).
Nearly a quarter century after BMP-2, in the form of Sofamor Danek’s (later Medtronic Spine) Infuse, which used a collagen carrier from Integra LifeSciences Corporation, was approved for use in spine fusion surgery as a bone graft material, at least FIVE breakthrough device designations have been granted to three companies for their very novel BMP-2 delivery systems.
What are those systems and why should we care?
Nanoclay Gel rhBMP-2 Carrier
Starting with the most recent first, Renovos Biologics is working on a nanoclay bone fusion gel, brand named RENOVITE® BMP-2 which has the potential to deliver an improved (safer, more effective, lower dose) bone morphogenic graft implant.
To be clear, it is difficult, to put it mildly, to use rhBMP-2 as a bone graft without a carrier. First, rhBMP-2 has a short half-life. To be effective without a carrier, it’s entirely possible that surgeons would have to administer high dosages (easily hundreds of times higher than naturally occurring BMP-2) repeatedly in order to achieve fusion. Second, rh-BMP-2 has been shown in the literature to cause uncontrollable bone regeneration.
Also, rhBMP-2 is instable under thermal or fluctuant pH conditions. So, without a carrier, rhBMP-2 would not meet the exacting requirements of spine fusion surgery. More than that, the right carrier can significantly improve both the efficacy and safety of rhBMP-2.
UK-based Renovos Biologics is using a very innovative material, nanoclay, to hold and release its rhBMP-2. Nanoclay is a 2D nanomaterial for bone tissue engineering which is a highly versatile material with multiple possible functions including osteoinductivity and controlled drug release capabilities.
A mouse study (“Nanoclay Promotes Mouse Cranial Bone Regeneration Mainly through Modulating Drug Binding and Sustained Release”) published in the December 2020 issue of Applied Materials Today, found that binding rhBMP-2 directly to a nanoclay scaffold provided protection from BMP-2 and delivered a sustained release.
The study was conducted at the Iowa Institute for Oral Health Research, University of Iowa College of Dentistry.
Quoting directly from the published study: “To determine the role of NS [nanosilicates] in osteoblastic differentiation and bone formation, we used the mouse calvarial-derived pre-osteoblasts (MC3T3-E1) and a clinically-relevant mouse cranial bone defect model. Instead of a hydrogel, we prepared biomimetic 3D gelatin nanofibrous scaffolds (GF) and NS-blended composite scaffolds (GF/NS) to determine the essential role of NS in critical low-dose (0.5 μg per scaffold) of BMP-2-induced cranial bone regeneration.”
“In contrast to ‘osteoinductivity’, our data indicated that NS could enable single-dose of BMP-2, promoting significant osteoblastic differentiation while multiple-dose of BMP-2 (without NS) was required to achieve similar efficacy.”
“Consistently, our in vivo data indicated that only BMP-2/NS direct binding treatment was able to repair the large mouse cranial bone defects after 6 weeks of transplantation while neither BMP-2, NS alone, nor BMP-2 released from GF/NS scaffolds was sufficient to induce significant cranial bone defect repair.”
According to Renovos Biologics, “RENOVITE® BMP-2, based on a proprietary synthetic nanoclay gel, is in development as a safer and more effective alternative to currently available bone graft materials. The easy-to-use, injectable gel allows precise, localised bone formation at the target site. It contains BMP-2, a growth factor which promotes in-growth of bone forming cells. The nanoclay gel enables safe, highly targeted bone fusion, as it does not leach BMP-2, with the gel biodegrading as new bone forms.”
LDGraft®
Locate Bio, a spin-out from the University of Nottingham and backed by Mercia Asset Management PLC and BGF, has created a novel osteoconductive scaffold which controls and extends the release of rhBMP-2. The carrier does not contain any liquid phase or surface attached rhBMP-2. Instead, Locate Bio encapsulates rhBMP-2 within a proprietary polymer scaffold system which degrades over several weeks, continuously releasing the rhBMP-2 as it does so.
John von Benecke, Locate Bio CEO, said: “According to the World Health Organisation, chronic low back pain is already the leading cause of disability worldwide, with 570 million prevalent cases worldwide. With a rapidly ageing global population, there is now an urgent need for next-generation products to relieve suffering and improve the quality of life for millions of patients.”
“We are delighted therefore to have been granted a Breakthrough Device designation from the FDA for LDGraft, our exciting controlled and extended-release rhBMP-2 scaffold for spinal fusion.”
“Having recently completed our final preclinical work, we are looking forward to progressing LDGraft into human clinical trials later this year [2023] and ultimately, regulatory approval.”
OsteoAdapt SP (AMP2 + ReBOSSIS Calcium Fibers)
Frederick, Maryland-based Theradaptive uses a calcium fiber-based scaffolding upon which it is binding its own form of BMP-2, which it has brand named AMP2. Early in 2023, the company’s researchers presented an abstract which provided evidence of AMP2’s efficacy and safety in rabbit posterior lumbar fusion (PLF) and sheep interbody fusion models.
The abstract was presented at the Orthopaedic Research Society’s annual meeting in Dallas in early 2023. The abstract showed how coating an implant with its proprietary material-binding osteoinductive AMP2 protein resulted in precise localization of bone formation and consistent spinal fusion without off-target effects.
Researchers observed 100% fusion compared to the 60% associated with current autograft technologies in PLF.
By re-engineering rhBMP-2 to create a material-binding protein variant AMP2, Theradaptive has created a protein that induces bone-growth more potently and in a more precisely localized way than rhBMP-2, thus vastly reducing off-target effects. The Theradaptive process binds AMP2 to ReBOSSIS, a 510K-approved implant material, to create its OsteoAdapt SP Spinal Fusion implant, a safer alternative to commercially available rhBMP-2.
In this study, scientists from Theradaptive and the University of Iowa assessed the ability of OsteoAdapt SP to induce spinal fusion in rabbit posterolateral and sheep interbody models. Twelve rabbits underwent single level posterolateral fusion, using OsteoAdapt SP rather than autograft.
Three sheep underwent two-level lumbar interbody fusion using high or low dose OsteoAdapt SP.
In the rabbit PLF model, OsteoAdapt SP demonstrated an impressive 100% fusion, compared to the 60% associated with iliac crest bone grafts, the current best practice.
In the pilot sheep interbody model, CTs showed an increase in density of new bone formation over time with evidence of bridging bone by 4-8 weeks at the high dose and 8-12 weeks at the low dose.
Theradaptive CEO and Founder Dr. Luis Alvarez, Ph.D. sees these results as an encouraging step towards human clinical trials: “Current autograft treatments are painful, they risk adverse events, and they only work around 60% of the time.”
“Seeing OsteoAdapt SP beat the current standard of care in these well accepted models so convincingly in preclinical trials gives us optimism that targeted regenerative technology like AMP2 will improve outcomes for patients who currently have few options. We expect to start first in human trials later this year [2023].”
Douglas Fredericks, Director of the University of Iowa Bone Healing Research Laboratory, said “AMP2 promises a breakthrough to the problem of integrating spinal fusion implants with living tissues. Targeted delivery of biologics harnesses the excellent bone-forming capabilities of current biologics, while limiting off-target responses. Implants like OsteoAdapt SP simplify product preparation and, crucially, deliver an extremely high fusion rate as this study shows.”
The Future
Clearly, BMP-based bone grafting is taking a big turn—led by three small technology companies—two in the UK and one in the U.S.
All BMP-2 bone grafting products require an FDA PMA (premarket approval) for commercialization in the United States. All three young companies are working their ways through that gauntlet. If successful, and I think one or more will be, then Medtronic’s Infuse, the market leader in advanced osteogenetic bone grafts will have its first direct BMP competitor. As to when, my guess is within three years. Stay tuned, for sure.
