Delivery of Osteogenic Regulatory Growth Factors - Engineered Bone: Tissue Engineering Intelligence Unit - page 108

Rationale for Designing an Effective Growth Factor Carrier
One of the most important advances in biotechnology has been the production of large
quantities of highly purified proteins by recombinant cDNA technology. However, further
progress is needed as direct injection of growth factors has limited efficacy and a prolonged
local delivery of growth factors is often needed to incur a biological response. Such a delivery
can only be achieved through the use of controlled release systems due to the short half-life of
growth factors, usually in the order of minutes.
As early as 1982, Urist et al then Lucas et al demonstrated the necessity for carrier material
that can deliver the water-soluble osteoinductive factors. When implanted alone, the proteins
were completely unable to induce the osteogenic cascade into a muscle pouch although capable
of inducing cartilage in in-vitro assay systems. 16 The authors postulated that these proteins
diffused too rapidly for induction to occur. 17,18 The combination of a carrier system with the
growth factor appeared to be essential for the regeneration and ingrowth of bone tissue.
Supra-physiological doses of single factors are generally required to induce bone: in the
order of milligrams for endogeneously extracted BMPs and micrograms for recombinant BMPs. 19
These amounts are several orders of magnitude higher than that which are present in bone
(typically µ g quantities per kg of bone). 20 An optimised delivery system might be able to im-
prove the osteopotency of the device while reducing the amount of implanted BMP. This fact
is of major importance when considering the clinical consequences of using very large amounts
of growth factor. Very little is known at this moment about the potentially adverse effects of
systemic diffusion of BMPs and thus, it is clinically prudent to minimise therapeutic quantity.
Obviously, another advantage in decreasing BMP dosage is to reduce the cost of the implanted
device.
Controlled release devices for drug delivery are well known in pharmacology. These systems
should allow a local release at therapeutic levels over periods long enough to allow bone tissue
regeneration. Properties of a BMP carrier system will comprise numerous specifications. Suc-
cessful delivery of inductive proteins require all the following features: (1) a controlled release,
(2) an adequate amount delivered to the inducible cells, (3) a rapid ingrowth of host tissue into
the carrier, (4) biocompatibility and safety of the implant material, (5) adequate resorption of
the implant and (6) reproducibility of the carrier properties. Additionally, the ideal matrix
should also be malleable, sterilizable and easily manufactured.
From the preclinical studies, it appears that a sustained release of the osteoinductive pro-
teins may be the most satisfactory means and poses the least risk from unanticipated side
effects. Indeed, BMPs are bone cell differentiation factors that are appropriately classified as
morphogens. 21 In this respect, BMPs obey the laws of diffusion and form concentration gradi-
ents with patterns that are tissue specific. The development of BMP delivery systems capable of
precisely and predictably releasing the morphogen in effective concentration gradients over the
duration of wound healing is quite essential for the implantation of BMP in patients.
Selecting a matrix which has most or even some of these desirable properties has been the
principal problem faced by pharmaceutical companies developing BMPs for clinical applica-
tion. As a result, extracted and recombinant BMPs have been evaluated using a large variety of
carriers that are made of natural and synthetic materials.
Herein, this chapter reviews some of the major properties of the “ ideal “ controlled delivery
system.
Scaffold Properties
BMP induced osteogenesis and chondrogenesis is highly dependent upon the carrier: the
carrier acts not only as a drug delivery system but also as a permissive environment into which
bone cells would migrate, proliferate, differentiate and begin the process of depositing bone
matrix (i.e., osteoconduction). 22 A cell substratum requires specific biochemical (molecules of
the extracellular matrix), physicochemical (surface free energy, charge and hydrophobicity) as
well as geometrical properties (three dimensional, interconnected porosity). 23 Numerous